JP2020079281A - Topical formulation for jak inhibitor - Google Patents
Topical formulation for jak inhibitor Download PDFInfo
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- JP2020079281A JP2020079281A JP2020018063A JP2020018063A JP2020079281A JP 2020079281 A JP2020079281 A JP 2020079281A JP 2020018063 A JP2020018063 A JP 2020018063A JP 2020018063 A JP2020018063 A JP 2020018063A JP 2020079281 A JP2020079281 A JP 2020079281A
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Abstract
Description
関連出願の相互参照
本出願は、参照によりその全体を本明細書に組み込むものとする、2010年5月21日に出願された米国特許仮出願第61/347,132号の優先権の利益を主張するものである。
CROSS REFERENCE TO RELATED APPLICATIONS This application benefits from the priority of US Provisional Application No. 61/347,132, filed May 21, 2010, which is hereby incorporated by reference in its entirety. I argue.
本発明は、(R)−3−シクロペンチル−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]プロパンニトリル、またはその薬剤的に許容可能な塩を含む局所的皮膚適用のための医薬製剤および皮膚障害の治療における使用に関する。 The present invention provides (R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutical agent thereof. Relates to pharmaceutical formulations for topical dermal application comprising pharmaceutically acceptable salts and use in the treatment of skin disorders.
蛋白質キナーゼ(PK)は、細胞増殖、生存、分化、器官形成、形態形成、血管新生、組織修復、および再生などが挙げられる多くの生物学的プロセスを調節する。蛋白質キナーゼはまた、癌を含む数多くのヒトの疾患において特殊な役割を果たす。低分子量ポリペプチドまたは糖蛋白質であるサイトカインは、敗血症に対する宿主炎症反応に関与する多くの経路を調節する。サイトカインは、細胞分化、増殖および活性化に影響を及ぼし、宿主が病原体に対して適切に応答できるように、炎症誘発性応答および抗炎症応答の双方を調節することができる。広範なサイトカインのシグナル伝達には、蛋白質チロシンキナーゼのJanusキナーゼファミリー(JAK)およびシグナル伝達兼転写活性化因子(STAT)が関与する。4つの既知の哺乳類JAKがあり、これらはJAK1(Janusキナーゼ−1)、JAK2、JAK3(Janusキナーゼ、白血球;JAKL;およびL−JAKとしても知られる)ならびにTYK2(蛋白質−チロシンキナーゼ2)である。 Protein kinases (PKs) regulate many biological processes including cell proliferation, survival, differentiation, organogenesis, morphogenesis, angiogenesis, tissue repair, and regeneration. Protein kinases also play a special role in many human diseases, including cancer. Cytokines, which are low molecular weight polypeptides or glycoproteins, regulate many pathways involved in the host inflammatory response to sepsis. Cytokines can influence cell differentiation, proliferation and activation and regulate both pro-inflammatory and anti-inflammatory responses so that the host can respond appropriately to pathogens. A wide range of cytokine signaling involves the Janus kinase family of protein tyrosine kinases (JAK) and the signal transduction and activator of transcription (STAT). There are four known mammalian JAKs, JAK1 (Janus kinase-1), JAK2, JAK3 (Janus kinase, leukocytes; JAKL; also known as L-JAK) and TYK2 (protein-tyrosine kinase 2). ..
サイトカイン刺激免疫応答および炎症応答は、疾患の病理発生機徐、すなわち、免疫系の抑制に起因する重症複合型免疫不全(SCID)のような病理に寄与し、その一方で過活動または不適切な免疫/炎症応答は、自己免疫疾患の病理(例えば、喘息、全身性エリテマトーデス、甲状腺炎、心筋炎)、ならびに皮膚硬化症および骨関節炎のような疾病に寄与する(非特許文献1)。 Cytokine-stimulated immune and inflammatory responses contribute to the pathogenesis of disease, ie, pathologies such as severe combined immunodeficiency (SCID) due to suppression of the immune system, while overactive or inappropriate. The immune/inflammatory response contributes to the pathology of autoimmune diseases (eg, asthma, systemic lupus erythematosus, thyroiditis, myocarditis) and diseases such as skin sclerosis and osteoarthritis (Non-Patent Document 1).
JAKの発現の不全は、多くの疾患状態に関連する。例えば、Jak−/−マウスは、出生時に発育不良であり、授乳に失敗し、更に周産期に死亡する(非特許文献2)。Jak2−/−マウス胚は貧血性であり、最終的赤血球生成の不在のために、交尾後12.5日周辺で死亡する。 Impaired expression of JAK is associated with many disease states. For example, Jak −/− mice have poor development at birth, fail to feed, and die during the perinatal period (Non-patent Document 2). Jak2−/− mouse embryos are anemic and die around 12.5 days after mating due to the absence of terminal erythropoiesis.
JAK/STAT経路、および特に4つのJAKの全ては、喘息反応、慢性塞栓性呼吸器系疾患、気管支炎、および下気道の他の関連する炎症性疾患の病理発生機徐において影響を及ぼすと考えられている。JAKを介してシグナルを送る複数のサイトカインが、古典的なアレルギー反応であろうとなかろうと、鼻および副鼻腔に発症する疾患(例えば、鼻炎および副鼻腔炎)のような上気道の炎症性疾患/症状に関連付けられている。JAK/STAT経路はまた、目および慢性アレルギー反応の炎症性疾患/症状に関係があるとされている。 The JAK/STAT pathway, and in particular all four JAKs, are thought to affect the pathogenesis of asthmatic reactions, chronic embolic respiratory disease, bronchitis, and other related inflammatory diseases of the lower respiratory tract Has been. Inflammatory diseases of the upper respiratory tract/such as those that develop in the nose and sinuses (eg rhinitis and sinusitis), with or without classical allergic reactions, by multiple cytokines signaling via JAK/ Associated with symptoms. The JAK/STAT pathway has also been implicated in inflammatory diseases/conditions of the eye and chronic allergic reactions.
癌におけるJAK/STATの活性化は、サイトカイン刺激(例えばIL−6またはGM−CSF)によってまたはSOCS(サイトカインシグナル抑制因子)またはPIAS(活性化STATの蛋白質阻害剤)のようなJAKシグナル伝達の内因性サプレッサーの減少によって生じ得る(非特許文献3)。STATシグナル伝達の活性化、ならびにJAKの下流の他の経路(例えば、Akt)の活性化は、多くの癌の型での予後不良に関連付けられている(非特許文献4)。JAK/STATを介してシグナル伝達する循環性サイトカインの上昇したレベルは、悪液質および/または慢性疲労の原因として影響を及ばす。このように、JAK阻害は、潜在的抗腫瘍活性を超えて作用を及ぼすという理由で、癌患者にとって有益であり得る。 Activation of JAK/STATs in cancer is caused by cytokine stimulation (eg, IL-6 or GM-CSF) or by endogenous JAK signaling such as SOCS (cytokine signal suppressor) or PIAS (protein inhibitor of activated STAT). It can be caused by a decrease in sex suppressor (Non-patent Document 3). Activation of STAT signaling, as well as activation of other pathways downstream of JAK (eg, Akt) has been associated with poor prognosis in many cancer types (Non-Patent Document 4). Elevated levels of circulating cytokines that signal through JAK/STAT affect cachexia and/or the cause of chronic fatigue. Thus, JAK inhibition may be beneficial to cancer patients because it acts beyond the potential anti-tumor activity.
JAKキナーゼの阻害はまた、乾癬のような皮膚免疫疾患、および皮膚感作性を発症する患者で治療的有益性を有することが推定される。乾癬の最も一般的形態である尋常性乾癬では、活性化Tリンパ球がこの疾患およびそれに伴う乾癬斑の維持に重要であることが概ね認められいる(非特許文献5)。乾癬斑は、白血球および単球を含む著しい免疫浸潤、ならびに増大したケラチン細胞の増殖を伴う複数の表皮層を含有する。乾癬での免疫細胞の初期活性化は、不明確な機序によって起こるが、その維持は、種々のケモカインおよび成長因子に加えて、いくつかの炎症性サイトカインに依存すると考えられている(非特許文献6)。インターロイキン-2、−4、−6、−7、−12、−15、−18、および−23ならびにGM−CSFおよびIFNgを含むこれらの多くが、Janus(JAK)キナーゼを介してシグナル伝達する(非特許文献7)。したがって、JAKキナーゼのレベルでのシグナル伝達の遮断は、乾癬または皮膚の他の免疫疾患に冒された患者で治療的有益性をもたらし得る。 Inhibition of JAK kinases is also presumed to have therapeutic benefit in patients who develop skin immune disorders such as psoriasis, and skin sensitization. In psoriasis vulgaris, which is the most common form of psoriasis, it is generally accepted that activated T lymphocytes are important for the maintenance of this disease and its associated psoriatic plaques (Non-Patent Document 5). Psoriatic plaques contain multiple epidermal layers with marked immune infiltration, including leukocytes and monocytes, and increased keratinocyte proliferation. The initial activation of immune cells in psoriasis occurs by an unclear mechanism, but its maintenance is believed to depend on several inflammatory cytokines in addition to various chemokines and growth factors (Non-Patent Document 1). Reference 6). Many of these, including interleukin-2, -4, -6, -7, -12, -15, -18, and -23, and GM-CSF and IFNg, signal through Janus (JAK) kinases. (Non-patent document 7). Therefore, blockade of signaling at the level of JAK kinases may provide therapeutic benefit in patients affected by psoriasis or other immune disorders of the skin.
皮膚障害の治療におけるJAK阻害剤の有用性を考慮すると、改善されたJAK阻害剤の局所製剤が必要とされる。特に、良好な皮膚浸透特性を有するJAK阻害剤の安定で容易に塗布される製剤が必要とされる。本発明の製剤、ならびに本明細書に記載された方法は、これらの必要および他の目的に向けられるものである。 Given the utility of JAK inhibitors in the treatment of skin disorders, there is a need for improved topical formulations of JAK inhibitors. In particular, there is a need for stable and easily applied formulations of JAK inhibitors that have good skin penetration properties. The formulations of the present invention, as well as the methods described herein, are directed to these needs and other ends.
有力なJAK1/JAK2阻害剤である(R)−3−(4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル)−3−シクロペンチルプロパンニトリル、およびその薬剤的に許容可能な塩は、それぞれが参照によりその全体が本明細書に組み込まれる、米国特許第7,598,257号、米国特許公開第2009/0181959号、および同第2008/0312259号に先に記載されている。本発明は、局所投与および皮膚障害の治療に好適である(R)−3−(4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル)−3−シクロペンチルプロパンニトリルの水中油製剤を記載する。
したがって、本発明は、特に局所的皮膚適用のための医薬製剤を提供し、この医薬製剤は、
水中油エマルジョン、および
(R)−3−シクロペンチル−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]プロパンニトリルまたはその医薬上許容される塩である治療剤の治療的に有効な量
を含む。
Accordingly, the present invention provides a pharmaceutical formulation, especially for topical dermal application, which pharmaceutical formulation comprises
Oil-in-water emulsion, and (R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile or its pharmaceutically A therapeutically effective amount of a therapeutic agent that is an acceptable salt is included.
本発明はまた、本明細書に記載される医薬製剤を患者の皮膚の領域に適用することを含む、皮膚障害を治療する方法を提供する。 The present invention also provides a method of treating a skin disorder, comprising applying the pharmaceutical formulation described herein to the area of skin of a patient.
本発明はまた、必要とする患者の皮膚障害の治療での使用のために、本明細書で記載される医薬製剤を提供する。 The present invention also provides the pharmaceutical formulations described herein for use in treating a skin disorder in a patient in need thereof.
本発明はまた、必要とする患者の皮膚障害の治療で使用のための医薬品の調製の目的での、本明細書で記載される医薬製剤の使用を提供する。 The invention also provides the use of a pharmaceutical formulation as described herein for the purpose of preparing a medicament for use in treating a skin disorder in a patient in need thereof.
本発明の1つ以上の実施形態の詳細が、添付の図面および以下の説明で記載される。
本発明の他の特徴、目的、および利点は、この説明および図面、ならびに特許請求の範囲から明らかになるであろう。
The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below.
Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.
したがって、本発明は、特に局所的皮膚適用のための医薬製剤を提供し、この医薬製剤は、(R)−3−シクロペンチル−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]プロパンニトリル、またはその医薬上許容される塩の治療的に有効な量を含む。 Accordingly, the present invention provides a pharmaceutical formulation, especially for topical dermal application, which pharmaceutical formulation comprises (R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidine. -4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount.
いくつかの実施形態では、医薬製剤は、
水中油エマルジョン、および
(R)−3−シクロペンチル−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]プロパンニトリル、またはその医薬上許容される塩である治療剤の治療的に有効な量
を含む。
In some embodiments, the pharmaceutical formulation comprises
Oil-in-water emulsion, and (R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a medicament thereof It includes a therapeutically effective amount of the therapeutic agent, which is a top acceptable salt.
いくつかの実施形態では、エマルジョンは、水、油成分および乳化剤成分を含む。 In some embodiments, the emulsion comprises water, an oil component and an emulsifier component.
本明細書で使用するとき、「乳化剤成分」とは、一態様では、元素または粒子を、液体媒体内で懸濁状態に維持する物質または物質の混合物を指す。いくつかの実施形態では、乳化剤成分は、水と混合される場合、油相がエマルジョンを形成することをもたらす。いくつかの実施形態では、乳化剤成分は、1つ以上の非イオン性界面活性剤を指す。 As used herein, "emulsifier component" refers, in one aspect, to a substance or mixture of substances that maintains an element or particle in suspension in a liquid medium. In some embodiments, the emulsifier component causes the oil phase to form an emulsion when mixed with water. In some embodiments, the emulsifier component refers to one or more nonionic surfactant.
水中油製剤は、他の製剤と比較すると、より良好な外観、塗布性および安定性を有する。この製剤は、皮膚への製剤の良好な塗布性をもたらす粘稠性のクリーム状外観を有する。この良好な塗布性は、同様の無水製剤よりも良好な皮膚浸透性をもたらす。例えば、水中油製剤は、無水軟膏と比較した、24時間にわたるヒトの死体の皮膚の透過試験において、より高い累加量を示した。特定の理論に束縛されようとするものではないが、このより高い累加量は、透過のための増大した表面積をもたらす、無水軟膏と比較した場合の水中油製剤のより良好な塗布性によるものと考えられる。水中油製剤に関するより高い粘度もまた、低粘度の水中油ローションと比較すると、高粘度クリーム製剤がヒトの死体の皮膚の良好な透過を有するので、皮膚透過性に関して好ましいと思われる。 The oil-in-water formulation has a better appearance, coatability and stability when compared to other formulations. This formulation has a viscous creamy appearance which gives good application of the formulation to the skin. This good coatability results in better skin penetration than similar anhydrous formulations. For example, the oil-in-water formulation showed a higher cumulative dose in a 24 hour human cadaver skin permeation study compared to anhydrous ointment. Without wishing to be bound to any particular theory, this higher cumulative loading is attributed to the better coatability of the oil-in-water formulation when compared to anhydrous ointment, which results in increased surface area for permeation. Conceivable. The higher viscosities for oil-in-water formulations may also be preferable in terms of skin permeability as high viscosity cream formulations have good permeation of human cadaver skin when compared to low viscosity oil-in-water lotions.
本明細書に記載される水中油製剤は、アルミニウム管内で、25℃/相対湿度(RH)60%および40℃/RH75%にて保存される場合、3ヶ月の期間にわたって良好な安定性を有し、ならびに経時的に適切な粘度を維持することが確認された。これに比較すると、油中水製剤は、40℃で保存される場合、離液現象を示した(離液現象とは、エマルジョンからの液体の分離を意味する)。 The oil-in-water formulations described herein have good stability when stored in aluminum tubes at 25°C/60% relative humidity (RH) and 40°C/75% RH over a period of 3 months. , And it was confirmed that the appropriate viscosity was maintained over time. In comparison, the water-in-oil formulation exhibited syneresis when stored at 40° C. (synergy means the separation of liquid from the emulsion).
油中水製剤はまた、インビトロ試験において、時間経過とともにAPIが塩基中に溶解し、高度に変動する皮膚透過もたらし、ならびに製剤の強度の増加に伴う透過性の増加が欠如するために、本発明の製剤よりもあまり望ましくない。 The water-in-oil formulation is also present in the present invention due to the fact that the API dissolves in base over time resulting in highly variable skin permeation in in vitro studies, as well as the lack of increased permeability with increasing strength of the formulation. Less desirable than the other formulations.
新しく切除されたマウス皮膚による移送試験では、水中油製剤はまた、可溶化クリームの強度が0.5%w/wから1.5%w/wに増加される場合、増大した透過性の一般的傾向を示したが、一方このような傾向は、油中水製剤では見られなかった。したがって、油中水エマルジョンは、強度の増加に伴って増強する透過性の提供に関しては、いかなる利点も有さないと思われる。 In a transfer study with freshly excised mouse skin, the oil-in-water formulation also showed increased permeability generally when the strength of the solubilized cream was increased from 0.5% w/w to 1.5% w/w. However, such a tendency was not observed in the water-in-oil formulation. Therefore, water-in-oil emulsions do not appear to have any benefit in terms of providing enhanced permeability with increasing strength.
更に、本明細書に記載される製剤は、調合の反復可能なプロセスにより、製造が比較的簡単である。得られた製品は容易に包装される。この製剤は、良好な安定性と比較的一定の浸透性を有すると思われる。 Furthermore, the formulations described herein are relatively simple to manufacture due to the repeatable process of formulation. The product obtained is easily packaged. This formulation appears to have good stability and relatively constant permeability.
いくつかの実施形態では、油成分は、製剤の約10重量%〜約40重量%の量で存在する。 In some embodiments, the oil component is present in an amount of about 10% to about 40% by weight of the formulation.
いくつかの実施形態では、油成分は、製剤の約17重量%〜約27重量%の量で存在する。 In some embodiments, the oil component is present in an amount of about 17% to about 27% by weight of the formulation.
いくつかの実施形態では、油成分は、製剤の約20重量%〜約27%重量の量で存在する。 In some embodiments, the oil component is present in an amount of about 20% to about 27% by weight of the formulation.
いくつかの実施形態では、油成分は、ワセリン、脂肪アルコール、鉱油、トリグリセリド、およびシリコーン油から独立に選択される1つ以上の物質を含む。 In some embodiments, the oil component comprises one or more substances independently selected from petrolatum, fatty alcohols, mineral oils, triglycerides, and silicone oils.
いくつかの実施形態では、油成分は、白色ワセリン、セチルアルコール、ステアリルアルコール、軽質鉱油、中鎖トリグリセリド、およびジメチコーンから独立して選択される1つ以上の物質を含む。 In some embodiments, the oil component comprises one or more substances independently selected from white petrolatum, cetyl alcohol, stearyl alcohol, light mineral oil, medium chain triglycerides, and dimethicone.
いくつかの実施形態では、油成分は、密封剤成分を含む。 In some embodiments, the oil component comprises a sealant component.
いくつかの実施形態では、密封剤成分は、製剤の約2重量%〜約15重量%の量で存在する。 In some embodiments, the sealant component is present in an amount of about 2% to about 15% by weight of the formulation.
いくつかの実施形態では、密封剤成分は、製剤の約5重量%〜約10重量%の量で存在する。 In some embodiments, the sealant component is present in an amount of about 5% to about 10% by weight of the formulation.
本明細書で使用するとき、「密封剤成分」とは、角質層からの水の蒸発を防止することによって、経皮水損失(TEWL)を減少させる密封性膜を皮膚上に形成する疎水性薬剤または疎水性薬剤の混合物を指す。 As used herein, a "sealant component" refers to a hydrophobic, hydrophobic layer that forms an occlusive membrane on the skin that prevents evaporation of water from the stratum corneum, thereby reducing transepidermal water loss (TEWL). Refers to a drug or mixture of hydrophobic drugs.
いくつかの実施形態では、密封剤成分は、脂肪酸(例えばラノリン酸)、脂肪アルコール(例えば、ラノリンアルコール)、炭化水素油&ワックス(例えば、ワセリン)、多価アルコール(例えば、プロピレングリコール)、シリコーン(例えば、ジメチコーン)、ステロール(例えば、コレステロール)、植物または動物油脂(例えば、ココナッツバター)、植物ワックス(例えば、カルナウバ蝋)、およびワックスエステル(例えば、蜜蝋)から選択される1つ以上の物質を含む。 In some embodiments, the sealant component is a fatty acid (eg, lanolinic acid), a fatty alcohol (eg, lanolin alcohol), a hydrocarbon oil & wax (eg, petrolatum), a polyhydric alcohol (eg, propylene glycol), a silicone. One or more substances selected from (eg dimethicone), sterols (eg cholesterol), vegetable or animal fats (eg coconut butter), vegetable waxes (eg carnauba wax), and wax esters (eg beeswax). including.
いくつかの実施形態では、密封剤成分は、ラノリン脂肪アルコール、ラノリンアルコール、ワセリン、プロピレングリコール、ジメチコーン、コレステロール、ココアバター、カルナウバ蝋、および蜜蝋から選択される1つ以上の物質を含む。 In some embodiments, the sealant component comprises one or more substances selected from lanolin fatty alcohol, lanolin alcohol, petrolatum, propylene glycol, dimethicone, cholesterol, cocoa butter, carnauba wax, and beeswax.
いくつかの実施形態では、密封剤成分は、ワセリンを含む。 In some embodiments, the sealant component comprises petrolatum.
いくつかの実施形態では、密封剤成分は、白色ワセリンを含む。 In some embodiments, the sealant component comprises white petrolatum.
いくつかの実施形態では、油成分は、硬化剤成分を含む。 In some embodiments, the oil component comprises a hardener component.
いくつかの実施形態では、硬化剤成分は、製剤の約2重量%〜約8重量%の量で存在する。 In some embodiments, the curative component is present in an amount of about 2% to about 8% by weight of the formulation.
いくつかの実施形態では、硬化剤成分は、製剤の約3重量%〜約6重量%の量で存在する。 In some embodiments, the hardener component is present in an amount of about 3% to about 6% by weight of the formulation.
いくつかの実施形態では、硬化剤成分は、製剤の約4重量%〜約7重量%の量で存在する。 In some embodiments, the curative component is present in an amount of about 4% to about 7% by weight of the formulation.
本明細書で使用するとき、「硬化剤成分」という用語は、製剤の粘度および/または粘稠度を増加させる、或いは製剤のレオロジーを改善する物質または物質の混合物を指す。 As used herein, the term "hardener component" refers to a substance or mixture of substances that increases the viscosity and/or consistency of a formulation or improves the rheology of a formulation.
いくつかの実施形態では、硬化剤成分は、脂肪アルコールから独立して選択される1つ以上の物質を含む。 In some embodiments, the hardener component comprises one or more substances independently selected from fatty alcohols.
いくつかの実施形態では、硬化剤成分は、C12−20脂肪アルコールから独立して選択される1つ以上の物質を含む。 In some embodiments, the hardener component comprises one or more substances independently selected from C12-20 fatty alcohols.
いくつかの実施形態では、硬化剤成分は、C16−18脂肪アルコールから独立して選択される1つ以上の物質を含む。 In some embodiments, the hardener component comprises one or more substances independently selected from C 16-18 fatty alcohols.
いくつかの実施形態では、硬化剤成分は、セチルアルコールおよびステアリルアルコールから独立して選択される1つ以上の物質を含む。 In some embodiments, the hardener component comprises one or more substances independently selected from cetyl alcohol and stearyl alcohol.
いくつかの実施形態では、油成分は、皮膚軟化剤成分を含む。 In some embodiments, the oil component comprises an emollient component.
いくつかの実施形態では、皮膚軟化剤成分は、製剤の約5重量%〜約15重量%の量で存在する。 In some embodiments, the emollient component is present in an amount of about 5% to about 15% by weight of the formulation.
いくつかの実施形態では、皮膚軟化剤成分は、製剤の約7重量%〜約13重量%の量で存在する。 In some embodiments, the emollient component is present in an amount of about 7% to about 13% by weight of the formulation.
本明細書で使用するとき、「皮膚軟化剤」という用語は、皮膚を軟化または緩和するか、もしくは刺激性の内表面を緩和する薬剤を指す。 As used herein, the term "emollient" refers to an agent that softens or relieves the skin or relieves irritating inner surfaces.
いくつかの実施形態では、皮膚軟化剤は、鉱油およびトリグリセリドから独立して選択される1つ以上の物質を含む。 In some embodiments, emollients include one or more substances independently selected from mineral oils and triglycerides.
いくつかの実施形態では、皮膚軟化剤は、軽質鉱油および中鎖トリグリセリドから独立して選択される1つ以上の物質を含む。 In some embodiments, the emollient comprises one or more substances independently selected from light mineral oil and medium chain triglycerides.
いくつかの実施形態では、皮膚軟化剤は、軽質鉱油、中鎖トリグリセリド、およびジメチコーンから独立に選択される1つ以上の物質を含む。 In some embodiments, the emollient comprises one or more substances independently selected from light mineral oil, medium chain triglycerides, and dimethicone.
いくつかの実施形態では、水は、製剤の約35重量%〜約65重量%の量で存在する。 In some embodiments, water is present in an amount of about 35% to about 65% by weight of the formulation.
いくつかの実施形態では、水は、製剤の約40重量%〜約60重量%の量で存在する。 In some embodiments, water is present in an amount of about 40% to about 60% by weight of the formulation.
いくつかの実施形態では、水は、製剤の約45重量%〜約55重量%の量で存在する。 In some embodiments, water is present in an amount of about 45% to about 55% by weight of the formulation.
いくつかの実施形態では、乳化剤成分は、製剤の約1重量%〜9重量%の量で存在する。 In some embodiments, the emulsifier component is present in an amount of about 1% to 9% by weight of the formulation.
いくつかの実施形態では、乳化剤成分は、製剤の約2重量%〜6重量%の量で存在する。 In some embodiments, the emulsifier component is present in an amount of about 2% to 6% by weight of the formulation.
いくつかの実施形態では、乳化剤成分は、製剤の約3重量%〜5重量%の量で存在する。 In some embodiments, the emulsifier component is present in an amount of about 3% to 5% by weight of the formulation.
いくつかの実施形態では、乳化剤成分は、製剤の約4重量%〜7重量%の量で存在する。 In some embodiments, the emulsifier component is present in an amount of about 4% to 7% by weight of the formulation.
いくつかの実施形態では、医薬製剤は、乳化剤成分および硬化剤成分を含み、ここにおいて乳化剤成分と硬化剤成分との合計量は、製剤の少なくとも約8重量%である。 In some embodiments, the pharmaceutical formulation comprises an emulsifier component and a hardener component, wherein the total amount of emulsifier component and hardener component is at least about 8% by weight of the formulation.
いくつかの実施形態では、乳化剤成分は、グリセリル脂肪エステルおよびソルビタン脂肪エステルから独立して選択される1つ以上の物質を含む。 In some embodiments, the emulsifier component comprises one or more substances independently selected from glyceryl fatty esters and sorbitan fatty esters.
いくつかの実施形態では、乳化剤成分は、グリセリルステアレートおよびポリソルベート20から独立して選択される1つ以上の物質を含む。 In some embodiments, the emulsifier component comprises one or more substances independently selected from glyceryl stearate and polysorbate 20.
いくつかの実施形態では、医薬製剤は、安定化剤成分を更に含む。 In some embodiments, the pharmaceutical formulation further comprises a stabilizer component.
いくつかの実施形態では、安定化剤成分は、製剤の約0.05重量%〜約5重量%の量で存在する。 In some embodiments, the stabilizer component is present in an amount from about 0.05% to about 5% by weight of the formulation.
いくつかの実施形態では、安定化剤成分は、製剤の約0.1重量%〜約2重量%の量で存在する。 In some embodiments, the stabilizer component is present in an amount of about 0.1% to about 2% by weight of the formulation.
いくつかの実施形態では、安定化剤成分は、製剤の約0.3重量%〜約0.5重量%の量で存在する。 In some embodiments, the stabilizer component is present in an amount of about 0.3% to about 0.5% by weight of the formulation.
本明細書で使用するとき。「安定化剤成分」とは、医薬製剤の安定性および/または製剤中の成分の適合性を改良する物質または物質の混合物を指す。いくつかの実施形態では、安定化剤成分は、エマルジョンの凝集を防止し、水中油のエマルジョン中の液滴を安定化させる。 As used herein. "Stabilizer component" refers to a substance or mixture of substances that improves the stability of a pharmaceutical formulation and/or the compatibility of the components in the formulation. In some embodiments, the stabilizer component prevents emulsion flocculation and stabilizes droplets in an oil-in-water emulsion.
いくつかの実施形態では、安定化剤成分は、多糖類から独立して選択される1つ以上の物質を含む。 In some embodiments, the stabilizer component comprises one or more substances independently selected from polysaccharides.
いくつかの実施形態では、安定化剤成分は、キサンタンガムを含む。 In some embodiments, the stabilizer component comprises xanthan gum.
いくつかの実施形態では、医薬製剤は、溶媒成分を更に含む。 In some embodiments, the pharmaceutical formulation further comprises a solvent component.
いくつかの実施形態では、溶媒成分は、製剤の約10重量%〜35重量%の量で存在する。 In some embodiments, the solvent component is present in an amount of about 10% to 35% by weight of the formulation.
いくつかの実施形態では、溶媒成分は、製剤の約15重量%〜30重量%の量で存在する。 In some embodiments, the solvent component is present in an amount of about 15% to 30% by weight of the formulation.
いくつかの実施形態では、溶媒成分は、製剤の約20重量%〜25重量%の量で存在する。 In some embodiments, the solvent component is present in an amount of about 20% to 25% by weight of the formulation.
本明細書で使用するとき、「溶媒成分」という用語は、製剤中で(R)−3−(4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル)−3−シクロペンチルプロパンニトリルまたは他の物質を溶解させることが可能な液体物質または液体物質の混合物を指す。いくつかの実施形態では、溶媒成分は、その中で(R)−3−(4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル)−2−シクロペンチルプロパンニトリル、またはその医薬上許容される塩が適切な溶解度を有する液体物質または液体物質の混合物である。例えば、(R)−3−(4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル)−3−シクロペンチルプロパンニトリル(遊離塩基)またはそのリン酸塩の溶解度が、表21に報告されている。いくつかの実施形態では、その中で(R)−3−(4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル)−3−シクロペンチルプロパンニトリル、またはその医薬上許容される塩(どれが使用されても)が、実施例4に記載されているように測定される場合、少なくとも10mg/mLまたはそれ以上、少なくとも15mg/mLまたはそれ以上、もしくは少なくとも約20mg/mLまたはそれ以上の溶解度を有するような物質またはその混合物である。 As used herein, the term "solvent component" refers to (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole-in the formulation. 1-yl)-3-cyclopentylpropanenitrile refers to a liquid substance or mixture of liquid substances capable of dissolving other substances. In some embodiments, the solvent component is (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-. 2-Cyclopentylpropanenitrile, or a pharmaceutically acceptable salt thereof, is a liquid substance or mixture of liquid substances having suitable solubility. For example, (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile (free base) or phosphorus thereof. The acid salt solubilities are reported in Table 21. In some embodiments, therein is (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropane. At least 10 mg/mL or more, at least 15 mg/mL or more when the nitrile, or a pharmaceutically acceptable salt thereof (whichever is used), is measured as described in Example 4. , Or a substance or mixture thereof having a solubility of at least about 20 mg/mL or higher.
いくつかの実施形態では、溶媒成分は、アルキレングリコールおよびポリアルキレングリコールから独立して選択される1つ以上の物質である。 In some embodiments, the solvent component is one or more substances independently selected from alkylene glycols and polyalkylene glycols.
いくつかの実施形態では、溶媒成分は、プロピレングリコールおよびポリエチレングリコールから独立して選択される1つ以上の物質である。 In some embodiments, the solvent component is one or more substances independently selected from propylene glycol and polyethylene glycol.
いくつかの実施形態では、治療剤は、遊離塩基を基準にして、製剤の約0.5重量%〜約1.5重量%の量で存在する。 In some embodiments, the therapeutic agent is present in an amount of about 0.5% to about 1.5% by weight of the formulation, based on the free base.
いくつかの実施形態では、治療剤は、遊離塩基を基準にして、製剤の約0.5重量%の量で存在する。 In some embodiments, the therapeutic agent is present in an amount of about 0.5% by weight of the formulation, based on the free base.
いくつかの実施形態では、治療剤は、遊離塩基を基準にして、製剤で約1重量%の量で存在する。 In some embodiments, the therapeutic agent is present in an amount of about 1% by weight of the formulation, based on the free base.
いくつかの実施形態では、治療剤は、遊離塩基を基準にして、製剤の約1.5重量%の量で存在する。 In some embodiments, the therapeutic agent is present in an amount of about 1.5% by weight of the formulation, based on the free base.
いくつかの実施形態では、治療剤は、(R)−3−シクロペンチル−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]プロパンニトリルリン酸塩である。 In some embodiments, the therapeutic agent is (R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]. Propane nitrile phosphate.
いくつかの実施形態では、医薬製剤は、
製剤の約35重量%〜約65重量%の水、
製剤の約10重量%〜約40重量%の油成分、
製剤の約1重量%〜約9重量%の乳化剤成分、
製剤の約10重量%〜約35重量%の溶媒成分、
製剤の約0.05重量%〜約5重量%の安定化剤成分、および
遊離塩基を基準にして、製剤の約0.5重量%〜約1.5重量%の(R)−3−シクロペンチル−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]プロパンニトリル、またはその医薬上許容される塩
を含む。
In some embodiments, the pharmaceutical formulation comprises
From about 35% to about 65% water by weight of the formulation,
About 10% to about 40% by weight of the formulation of the oil component,
About 1% to about 9% by weight of the formulation of an emulsifier component,
About 10% to about 35% by weight of the formulation of the solvent component,
From about 0.05% to about 5% by weight of the formulation of the stabilizer component and from about 0.5% to about 1.5% by weight of the formulation of (R)-3-cyclopentyl, based on the free base. -3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof.
いくつかの実施形態では、医薬製剤は、
製剤の約40重量%〜約60重量%の水、
製剤の約15重量%〜約30重量%の油成分、
製剤の約2重量%〜約6重量%の乳化剤成分、
製剤の約15重量%〜約30重量%の溶媒成分、
製剤の約0.1重量%〜約2重量%の安定化剤成分、および
遊離塩基を基準にして、製剤の約0.5重量%〜約1.5重量%の(R)−3−シクロペンチル−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]プロパンニトリル、またはその医薬上許容される塩
を含む。
In some embodiments, the pharmaceutical formulation comprises
From about 40% to about 60% by weight of the formulation of water,
About 15% to about 30% by weight of the formulation of the oil component,
From about 2% to about 6% by weight of the formulation, an emulsifier component,
About 15% to about 30% by weight of the formulation of the solvent component,
From about 0.1% to about 2% by weight of the formulation of the stabilizer component, and from about 0.5% to about 1.5% by weight of the formulation, based on the free base, of (R)-3-cyclopentyl. -3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof.
いくつかの実施形態では、医薬製剤は、
製剤の約45重量%〜約55重量%の水、
製剤の約17重量%〜約27重量%の油成分、
製剤の約3重量%〜約5重量%の乳化剤成分、
製剤の約20重量%〜約25重量%の溶媒成分、
製剤の約0.3重量%〜約0.5重量%の安定化剤成分、および
遊離塩基を基準にして、製剤の約0.5重量%〜約1.5重量%の(R)−3−シクロペンチル−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]プロパンニトリル、またはその医薬上許容される塩
を含む。
In some embodiments, the pharmaceutical formulation comprises
About 45% to about 55% water by weight of the formulation,
From about 17% to about 27% by weight of the formulation of the oil component,
From about 3% to about 5% by weight of the formulation, an emulsifier component,
About 20% to about 25% by weight of the formulation of the solvent component,
From about 0.3% to about 0.5% by weight of the formulation of the stabilizer component, and from about 0.5% to about 1.5% by weight of the formulation, based on the free base, of (R)-3. -Cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof.
いくつかの実施形態では、医薬製剤は、
製剤の約45重量%〜約55重量%の水、
製剤の約17重量%〜約27重量%の油成分、
製剤の約4重量%〜約7重量%の乳化剤成分、
製剤の約20重量%〜約25重量%の溶媒成分、
製剤の約0.3重量%〜約0.5重量%の安定化剤成分、および
遊離塩基を基準にして、製剤の約0.5重量%〜約1.5重量%の(R)−3−シクロペンチル−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]プロパンニトリル、またはその医薬上許容される塩
を含む。
In some embodiments, the pharmaceutical formulation comprises
About 45% to about 55% water by weight of the formulation,
From about 17% to about 27% by weight of the formulation of the oil component,
From about 4% to about 7% by weight of the formulation, an emulsifier component,
About 20% to about 25% by weight of the formulation of the solvent component,
From about 0.3% to about 0.5% by weight of the formulation of the stabilizer component, and from about 0.5% to about 1.5% by weight of the formulation, based on the free base, of (R)-3. -Cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof.
いくつかの実施形態では、
油成分は、ワセリン、脂肪アルコール、鉱油、トリグリセリド、およびジメチコーンから独立して選択される1つ以上の物質を含み、
乳化剤成分は、グリセリル脂肪酸およびソルビタン脂肪エステルから独立して選択される1つ以上の物質を含み、
溶媒成分は、アルキレングリコールおよびポリアルキレングリコールから独立して選択される1つ以上の物質を含み、
安定化剤は、多糖類から独立して選択される1つ以上の物質を含む。
In some embodiments,
The oil component comprises one or more substances independently selected from petrolatum, fatty alcohols, mineral oil, triglycerides, and dimethicone,
The emulsifier component comprises one or more substances independently selected from glyceryl fatty acid and sorbitan fatty ester,
The solvent component comprises one or more substances independently selected from alkylene glycols and polyalkylene glycols,
Stabilizers include one or more substances independently selected from polysaccharides.
いくつかの実施形態では、
油成分は、白色ワセリン、セチルアルコール、ステアリルアルコール、軽質鉱油、中鎖トリグリセリド、およびジメチコーンから独立して選択される1つ以上の物質を含み、
乳化剤成分は、グリセリルステアレートおよびポリソルベート20から独立して選択される1つ以上の物質を含み、
溶媒成分は、プロピレングリコールおよびポリエチレングリコールから独立して選択される1つ以上の物質を含み、
安定化剤は、キサンタンガムを含む。
In some embodiments,
The oil component comprises one or more substances independently selected from white petrolatum, cetyl alcohol, stearyl alcohol, light mineral oil, medium chain triglycerides, and dimethicone,
The emulsifier component comprises one or more substances independently selected from glyceryl stearate and polysorbate 20;
The solvent component comprises one or more substances independently selected from propylene glycol and polyethylene glycol,
Stabilizers include xanthan gum.
いくつかの実施形態では、医薬製剤は、
製剤の約35重量%〜約65重量%の水、
製剤の約2重量%〜約15重量%の密封剤成分、
製剤の約2重量%〜8重量%の硬化剤成分、
製剤の約5重量%〜約15重量%の皮膚軟化剤成分、
製剤の約1重量%〜約9重量%の乳化剤成分、
製剤の約0.05重量%〜約5重量%の安定化剤成分、
製剤の約10重量%〜約35重量%の溶媒成分、および
遊離塩基を基準にして、製剤の約0.5重量%〜約1.5重量%の(R)−3−シクロペンチル−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]プロパンニトリル、またはその医薬上許容される塩
を含む。
In some embodiments, the pharmaceutical formulation comprises
From about 35% to about 65% water by weight of the formulation,
About 2% to about 15% by weight of the formulation of the sealant component,
About 2% to 8% by weight of the formulation of the hardener component,
About 5% to about 15% by weight of the formulation, an emollient component,
About 1% to about 9% by weight of the formulation of an emulsifier component,
From about 0.05% to about 5% by weight of the formulation of a stabilizer component,
About 10% to about 35% by weight of the formulation of the solvent component, and about 0.5% to about 1.5% by weight of the formulation of (R)-3-cyclopentyl-3-[, based on the free base. 4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof.
いくつかの実施形態では、医薬製剤は、
製剤の約40重量%〜約60重量%の水、
製剤の約5重量%〜約10重量%の密封剤成分、
製剤の約2重量%〜8重量%の硬化剤成分、
製剤の約7重量%〜約12重量%の皮膚軟化剤成分、
製剤の約2重量%〜約6重量%の乳化剤成分、
製剤の約0.1重量%〜約2重量%の安定化剤成分、
製剤の約15重量%〜約30重量%の溶媒成分、および
遊離塩基を基準にして、製剤の約0.5重量%〜約1.5重量%の(R)−3−シクロペンチル−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]プロパンニトリル、またはその医薬上許容される塩
を含む。
In some embodiments, the pharmaceutical formulation comprises
From about 40% to about 60% by weight of the formulation of water,
About 5% to about 10% by weight of the formulation of the sealant component,
About 2% to 8% by weight of the formulation of the hardener component,
About 7% to about 12% by weight of the formulation, an emollient component,
From about 2% to about 6% by weight of the formulation, an emulsifier component,
From about 0.1% to about 2% by weight of the formulation of a stabilizer component,
About 15% to about 30% by weight of the formulation of the solvent component, and about 0.5% to about 1.5% by weight of the formulation of (R)-3-cyclopentyl-3-[, based on the free base. 4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof.
いくつかの実施形態では、医薬製剤は、
製剤の約45重量%〜約55重量%の水、
製剤の約5重量%〜約10重量%の密封剤成分、
製剤の約3重量%〜6重量%の硬化剤成分、
製剤の約7重量%〜約13重量%の皮膚軟化剤成分、
製剤の約3重量%〜約5重量%の乳化剤成分、
製剤の約0.3重量%〜約0.5重量%の安定化剤成分、
製剤の約20重量%〜約25重量%の溶媒成分、および
遊離塩基を基準にして、製剤の約0.5重量%〜約1.5重量%の(R)−3−シクロペンチル−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]プロパンニトリル、またはその医薬上許容される塩
を含む。
In some embodiments, the pharmaceutical formulation comprises
About 45% to about 55% water by weight of the formulation,
About 5% to about 10% by weight of the formulation of the sealant component,
A hardener component of about 3% to 6% by weight of the formulation,
About 7% to about 13% by weight of the formulation, an emollient component,
From about 3% to about 5% by weight of the formulation, an emulsifier component,
From about 0.3% to about 0.5% by weight of the formulation of a stabilizer component,
About 20% to about 25% by weight of the formulation of the solvent component, and about 0.5% to about 1.5% by weight of the formulation of (R)-3-cyclopentyl-3-[based on the free base. 4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof.
いくつかの実施形態では、医薬製剤は、
製剤の約45重量%〜約55重量%の水、
製剤の約5重量%〜約10重量%の密封剤成分、
製剤の約4重量%〜7重量%の硬化剤成分、
製剤の約7重量%〜約13重量%の皮膚軟化剤成分、
製剤の約4重量%〜約7重量%の乳化剤成分、
製剤の約0.3重量%〜約0.5重量%の安定化剤成分、
製剤の約20重量%〜約25重量%の溶媒成分、および
遊離塩基を基準にして、製剤の約0.5重量%〜約1.5重量%の(R)−3−シクロペンチル−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]プロパンニトリル、またはその医薬上許容される塩
を含む。
In some embodiments, the pharmaceutical formulation comprises
About 45% to about 55% water by weight of the formulation,
About 5% to about 10% by weight of the formulation of the sealant component,
A hardener component of about 4% to 7% by weight of the formulation,
About 7% to about 13% by weight of the formulation, an emollient component,
From about 4% to about 7% by weight of the formulation, an emulsifier component,
From about 0.3% to about 0.5% by weight of the formulation of a stabilizer component,
About 20% to about 25% by weight of the formulation of the solvent component, and about 0.5% to about 1.5% by weight of the formulation of (R)-3-cyclopentyl-3-[based on the free base. 4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof.
いくつかの実施形態では、医薬製剤は、
製剤の約45重量%〜約55重量%の水、
製剤の約7重量%の密封剤成分、
製剤の約4.5重量%〜5重量%の硬化剤成分、
製剤の約10重量%の皮膚軟化剤成分、
製剤の約4重量%〜約4.5重量%の乳化剤成分、
製剤の約0.4重量%の安定化剤成分、
製剤の約22重量%の溶媒成分、および
遊離塩基を基準にして、製剤の約0.5重量%〜約1.5重量%の(R)−3−シクロペンチル−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]プロパンニトリル、またはその医薬上許容される塩
を含む。
In some embodiments, the pharmaceutical formulation comprises
About 45% to about 55% water by weight of the formulation,
A sealant component of about 7% by weight of the formulation,
About 4.5% to 5% by weight of the formulation of a hardener component,
An emollient component of about 10% by weight of the formulation,
From about 4% to about 4.5% by weight of the formulation of the emulsifier component,
About 0.4% by weight of the formulation of a stabilizer component,
About 22% by weight of the formulation of the solvent component, and about 0.5% to about 1.5% by weight of the formulation of (R)-3-cyclopentyl-3-[4-(7H- Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof.
いくつかの実施形態では、硬化剤成分と皮膚軟化剤成分との合計量は、製剤の少なくとも8重量%である。 In some embodiments, the total amount of hardener component and emollient component is at least 8% by weight of the formulation.
いくつかの実施形態では、
密封剤成分はワセリンを含み、
硬化剤成分は、1つ以上の脂肪アルコールから独立して選択される1つ以上の物質を含み、皮膚軟化剤成分は、鉱油およびトリグリセリドから独立して選択される1つ以上の物質を含み、
乳化剤成分はグリセリル脂肪エステルおよびソルビタン脂肪エステルから独立して選択される1つ以上の物質を含み、
安定化剤成分は、多糖類から独立して選択される1つ以上の物質を含み、
溶媒成分は、アルキレングリコールおよびポリアルキレングリコールから独立して選択される1つ以上の物質を含む。
In some embodiments,
The sealant component includes petrolatum,
The hardener component comprises one or more substances independently selected from one or more fatty alcohols, the emollient component comprises one or more substances independently selected from mineral oils and triglycerides,
The emulsifier component comprises one or more substances independently selected from glyceryl fatty esters and sorbitan fatty esters,
The stabilizer component comprises one or more substances independently selected from polysaccharides,
The solvent component comprises one or more substances independently selected from alkylene glycols and polyalkylene glycols.
いくつかの実施形態では、
密封剤成分は白色ワセリンを含み、
硬化剤成分は、1つ以上のセチルアルコールおよびステアリルアルコールから独立して選択される1つ以上の物質を含み、
皮膚軟化剤成分は、軽質鉱油、中鎖トリグリセリド、およびジメチコーンから独立して選択される1つ以上の物質を含み、
乳化剤成分はグリセリルステアレートおよびポリソルベート20から独立して選択される1つ以上の物質を含み、
安定化剤成分は、キサンタンガムを含み、
溶媒成分は、プロピレングリコールおよびポリエチレングリコールから独立して選択される1つ以上の物質を含む。
In some embodiments,
The sealant component includes white petrolatum,
The hardener component comprises one or more substances independently selected from one or more cetyl alcohol and stearyl alcohol,
The emollient component comprises one or more substances independently selected from light mineral oil, medium chain triglycerides, and dimethicone,
The emulsifier component comprises one or more substances independently selected from glyceryl stearate and polysorbate 20;
The stabilizer component includes xanthan gum,
The solvent component comprises one or more substances independently selected from propylene glycol and polyethylene glycol.
いくつかの実施形態では、医薬製剤は、抗菌性保存剤成分を更に含む。 In some embodiments, the pharmaceutical formulation further comprises an antimicrobial preservative component.
いくつかの実施形態では、抗菌性保存剤成分は、製剤の約0.05重量%〜約3重量%の量で存在する。 In some embodiments, the antimicrobial preservative component is present in an amount from about 0.05% to about 3% by weight of the formulation.
いくつかの実施形態では、抗菌性保存剤成分は、製剤の約0.1重量%〜約1重量%の量で存在する。 In some embodiments, the antimicrobial preservative component is present in an amount from about 0.1% to about 1% by weight of the formulation.
本明細書で使用するとき、「抗菌性保存剤成分」という表現は、製剤中での微生物成長を阻害する物質または物質の混合物である。 As used herein, the expression "antimicrobial preservative component" is a substance or mixture of substances that inhibits microbial growth in a formulation.
いくつかの実施形態では、抗菌性保存剤成分は、アルキルパラベンおよびフェノキシエタノールから独立して選択される1つ以上の物質を含む。 In some embodiments, the antimicrobial preservative component comprises one or more substances independently selected from alkylparabens and phenoxyethanol.
いくつかの実施形態では、抗菌性保存剤成分は、メチルパラベン、プロピルパラベン、およびフェノキシエタノールから独立して選択される1つ以上の物質である。 In some embodiments, the antimicrobial preservative component is one or more substances independently selected from methylparaben, propylparaben, and phenoxyethanol.
いくつかの実施形態では、医薬製剤は、キレート剤成分を更に含む。 In some embodiments, the pharmaceutical formulation further comprises a chelator component.
本明細書で使用するとき、「キレート剤成分」という表現は、金属イオンと強固に結合する能力を有する化合物または化合物の混合物を指す。 As used herein, the expression "chelator component" refers to a compound or mixture of compounds that has the ability to bind metal ions tightly.
いくつかの実施形態では、キレート剤成分は、エデト酸二ナトリウムを含む。 In some embodiments, the chelator component comprises disodium edetate.
(R)−3−(4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル)−3−シクロペンチルプロパンニトリルは、それぞれが参照によりその全体が本明細書に組み込まれる、米国特許第7,598,257号および米国特許公開第2009/0181959号に記載されているように調製され得る。(R)−3−(4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル)−3−シクロペンチルプロパンニトリルの1:1リン酸塩は、参照によりその全体が本明細書に組み込まれる、米国特許公開第2008/0312259号に記載されているように調製され得る。 (R)-3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile is each referred to in its entirety by reference. It can be prepared as described in US Pat. No. 7,598,257 and US Publication No. 2009/0181959, incorporated herein. The 1:1 phosphate of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile is It can be prepared as described in US Patent Publication No. 2008/0312259, which is incorporated herein by reference in its entirety.
本発明の化合物はまた、本明細書に開示される化合物の医薬上許容される塩を含む。本明細書で使用するとき、「医薬上許容される塩」という用語は、本明細書に記載される化合物への医薬上許容される酸または塩基の付加によって形成される塩を指す。本明細書で使用するとき、「薬学的に許容可能」という表現は、毒物学的観点から薬学的適用での使用に対して許容可能であり、ならびに活性成分と不適切に相互作用しない物質を指す。医薬上許容される塩としては、限定されるものではないが酢酸、乳酸、クエン酸、ケイ皮酸、酒石酸、コハク酸、フマール酸、マレイン酸、マロン酸、マンデル酸、リンゴ酸、シュウ酸、プロピオン酸、塩酸、臭化水素酸、リン酸、硝酸、硫酸、グリコール酸、ピリビン酸、メタンスルホン酸、エタンスルホン酸、トリエンスルホン酸、サリチル酸、安息香酸、および同様に既知の許容可能な酸のような有機および無機酸から誘導された塩を含む単塩およびニ塩が挙げられるが、これらに限定されない。好適な塩のリストは、それぞれを参照によりその全体を本明細書に援用する、Remington’s Pharmaceutical Sciences,第17版.,Mack Publishing Company,Easton,Pa.,1985年,1418頁およびJournal of Pharmaceutical Science,66,2(1977年)で見ることができる。 The compounds of the present invention also include pharmaceutically acceptable salts of the compounds disclosed herein. The term "pharmaceutically acceptable salt" as used herein refers to salts formed by the addition of a pharmaceutically acceptable acid or base to the compounds described herein. As used herein, the phrase "pharmaceutically acceptable" refers to a substance that is acceptable for use in pharmaceutical applications from a toxicological point of view, as well as that does not inappropriately interact with the active ingredient. Point to. Pharmaceutically acceptable salts include, but are not limited to, acetic acid, lactic acid, citric acid, cinnamic acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malonic acid, mandelic acid, malic acid, oxalic acid, Of propionic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, glycolic acid, pyrivic acid, methanesulfonic acid, ethanesulfonic acid, trienesulfonic acid, salicylic acid, benzoic acid and likewise known acceptable acids. Such salts include, but are not limited to, mono- and di-salts, including salts derived from organic and inorganic acids. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th Edition, each of which is hereby incorporated by reference in its entirety. , Mack Publishing Company, Easton, Pa. , 1985, page 1418 and Journal of Pharmaceutical Science, 66, 2 (1977).
本明細書で記載される化合物は、例えば水和された状態のような溶媒和形態で存在してもよく、ならびに溶媒和されていない形態で存在してもよいこともまた理解されるであろう。本発明は、化合物のこのような溶媒和形態の全てを包含することも更に理解されるであろう。 It is also understood that the compounds described herein may exist in solvated forms as well, eg in the hydrated state, as well as in unsolvated forms. Let's do it. It will be further understood that the present invention includes all such solvated forms of the compounds.
本明細書で使用するとき、「製剤の重量%」とは、製剤中の成分のパーセント濃度が、重量/重量を基準にしていることを意味する。例えば、1%w/wの成分A=[(成分Aの質量)/(製剤の総質量)]×100である。 As used herein, "wt% of formulation" means that the percent concentration of ingredients in the formulation is based on weight/weight. For example, 1% w/w of component A=[(mass of component A)/(total mass of formulation)]×100.
本明細書で使用するとき、(R)−3−(4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル)−3−シクロペンチルプロパンニトリル、またはその医薬上許容される塩の「遊離塩基を基準とした製剤の重量%」とは、%w/wが、製剤総重量における(R)−3−(4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル)−3−シクロペンチルプロパンニトリルの重量に基づいて計算されることを意味する。例えば、「遊離塩基を基準とした0.5%w/w」の(R)−3−(4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル)−3−シクロペンチルプロパンニトリルリン酸塩とは、100gの製剤総重量に対して、0.66gの(R)−3−(4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル)−3−シクロペンチルプロパンニトリルリン酸塩が製剤中に存在することを意味する(これは、遊離塩基、すなわち(R)−3−(4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル)−3−シクロペンチルプロパンニトリルの0.5グラムと同等である)。 As used herein, (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile, Alternatively, the term “wt% of the preparation based on the free base” of the pharmaceutically acceptable salt thereof means that% w/w is (R)-3-(4-(7H-pyrrolo[2,2 in the total weight of the preparation. It is meant to be calculated based on the weight of 3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile. For example, "0.5% w/w based on free base" of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole-1. -Yl)-3-cyclopentylpropanenitrile phosphate means that 0.66 g of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidine- 4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate is present in the formulation (this is the free base, i.e. (R)-3-(4-( Equivalent to 0.5 grams of 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile).
いくつかの実施形態では、成分は、特定化された範囲で厳密に存在する(例えば用語「約」は存在しない)。いくつかの実施形態では、「約」は、数値のプラスまたはマイナス10%を意味する。 In some embodiments, components are strictly present in a specified range (eg, the term "about" is absent). In some embodiments, “about” means plus or minus 10% of a number.
理解されるように、本明細書で記載される医薬製剤のいくつかの成分は、複数の機能を有することができる。例えば、所与の物質が、乳化剤成分および安定化剤の双方として作用し得る。このような場合のいくつかでは、所与の成分の機能は、その特性が複数の機能をもたらすにしても、単一であると考えられ得る。いくつかの実施形態では、製剤の各成分は、異なる物質または物質の混合物を含む。 As will be appreciated, some components of the pharmaceutical formulations described herein can have multiple functions. For example, a given substance can act as both an emulsifier component and a stabilizer. In some of these cases, the function of a given component can be considered to be single, even though its properties provide multiple functions. In some embodiments, each component of the formulation comprises a different substance or mixture of substances.
本明細書で使用するとき、「成分」という用語は、物質または物質の混合物を意味し得る。 As used herein, the term “ingredient” may mean a substance or mixture of substances.
本明細書で使用するとき、「脂肪酸」という用語は、飽和されているまたは不飽和の脂肪族酸を指す。いくつかの実施形態では、脂肪酸は異なる脂肪酸の混合物中にある。いくつかの実施形態では、脂肪酸は、平均で約8〜約30個の炭素を有する。いくつかの実施形態では、脂肪酸は、平均で約12〜20個、14〜20個、または16〜18個の炭素を有する。好適な脂肪酸としては、限定されるものではないが、セチル酸、ステアリン酸、ラウリル酸、ミリスチン酸、エルカ酸、パルミチン酸、パルミトオレイン酸、カプリン酸、カプリル酸、オレイン酸、リノール酸、リノレイン酸、ヒドロキシステアリン酸、12−ヒドロキシステアリン酸、セトステアリン酸、イソステアリン酸、セスキオレイン酸、セスキ−9−オクタデカン酸、セスキイソオクタデカン酸、ベヘン酸、イソベヘン酸、およびアラキドン酸、またはこれらの混合物が挙げられる。 As used herein, the term “fatty acid” refers to a saturated or unsaturated aliphatic acid. In some embodiments, the fatty acids are in a mixture of different fatty acids. In some embodiments, the fatty acids have an average of about 8 to about 30 carbons. In some embodiments, the fatty acids have an average of about 12-20, 14-20, or 16-18 carbons. Suitable fatty acids include, but are not limited to, cetyl acid, stearic acid, lauric acid, myristic acid, erucic acid, palmitic acid, palmitooleic acid, capric acid, caprylic acid, oleic acid, linoleic acid, linolein. Acid, hydroxystearic acid, 12-hydroxystearic acid, cetostearic acid, isostearic acid, sesquioleic acid, sesqui-9-octadecanoic acid, sesquiisooctadecanoic acid, behenic acid, isobehenic acid, and arachidonic acid, or mixtures thereof. Can be mentioned.
本明細書で使用するとき、「脂肪アルコール」という用語は、飽和されているまたは不飽和の脂肪族アルコールを指す。いくつかの実施形態では、脂肪アルコールは、異なる脂肪アルコールの混合物中にある。いくつかの実施形態では、脂肪アルコールは、平均で約12〜約20個、約14〜約20個、または約16〜約18個の炭素を有する。好適な脂肪アルコールとしては、限定されるものではないが、ステアリルアルコール、ラウリルアルコール、パルミチルアルコール、セチルアルコール、カプリルアルコール、カプリリルアルコール、オレイルアルコール、リノレニルアルコール、アラキドンアルコール、ベヘニルアルコール、イソベヘニルアルコール、セラキルアルコール、キミルアルコール、およびリノレイルアルコール、またはこれらの混合物が挙げられる。 As used herein, the term “fatty alcohol” refers to a saturated or unsaturated fatty alcohol. In some embodiments, the fatty alcohol is in a mixture of different fatty alcohols. In some embodiments, fatty alcohols have an average of about 12 to about 20, about 14 to about 20, or about 16 to about 18 carbons. Suitable fatty alcohols include, but are not limited to, stearyl alcohol, lauryl alcohol, palmityl alcohol, cetyl alcohol, capryl alcohol, caprylyl alcohol, oleyl alcohol, linolenyl alcohol, arachidone alcohol, behenyl alcohol, isobehenyl alcohol. , Ceracyl alcohol, chimyl alcohol, and linoleyl alcohol, or mixtures thereof.
本明細書で使用するとき、単独または他の用語と組み合わせで使用されている「ポリアルキレングリコール」という用語は、オキシアルキレンモノマー単位を含有するポリマー、または異なるオキシアルキレンモノマー単位のコポリマーを指し、ここにおいて、アルキレン基は、2〜6個、2〜4個、または2〜3個の炭素原子を有する。本明細書で使用するとき、単独または他の用語と組み合わせで使用されている「オキシアルキレン」という用語は、式−O−アルキレン−の基を指す。いくつかの実施形態では、ポリアルキレングリコールはポリエチレングリコールである。 The term "polyalkylene glycol," as used herein, alone or in combination with other terms, refers to a polymer containing oxyalkylene monomer units or a copolymer of different oxyalkylene monomer units, wherein In, the alkylene group has 2 to 6, 2 to 4, or 2 to 3 carbon atoms. The term "oxyalkylene," as used herein, alone or in combination with other terms, refers to a group of formula -O-alkylene-. In some embodiments, the polyalkylene glycol is polyethylene glycol.
本明細書で使用するとき、「ソルビタン脂肪エステル」という用語は、ソルビタンまたはソルビトールおよび脂肪酸、および必要に応じて、ポリ(エチレングリコール)単位から誘導された生成物を包含し、ソルビタンエステルおよびポリエトキシル化ソルビタンエステルを包含する。いくつかの実施形態では、ソルビタン脂肪エステルは、ポリエトキシル化ソルビタンエステルである。 As used herein, the term “sorbitan fatty ester” includes sorbitan or sorbitol and fatty acids, and optionally products derived from poly(ethylene glycol) units, sorbitan ester and polyethoxyl. Sorbitan ester is included. In some embodiments, the sorbitan fatty ester is a polyethoxylated sorbitan ester.
本明細書で使用するとき、「ソルビタンエステル」という用語は、ソルビトールと少なくとも1つの脂肪酸とのエステル化から誘導された化合物、または化合物の混合物を指す。ソルビタンエステルを誘導するために有用な脂肪酸としては、限定されるものではないが、本明細書に記載されるような脂肪酸が挙げられる。好適なソルビタンエステルとしては、限定されるものではないが、Span(商標)シリーズ(Uniqemaから入手可能)が挙げられ、これはSpan20(ソルビタンモノラウレート)、40(ソルビタンモノパルミテート)、60(ソルビタンモノステアレート)、65(ソルビタントリステアレート)、80(ソルビタンモノオレエート)、および85(ソルビタントリオレエート)を含む。他の好適なソルビタンエステルとしては、参照によりその全体を本明細書に援用する、R.C.RoweおよびP.J.Shesky,Handbook of pharmaceutical excipients,(2006年),第5版に列挙されているものを含む。 As used herein, the term "sorbitan ester" refers to a compound, or mixture of compounds, derived from the esterification of sorbitol with at least one fatty acid. Fatty acids useful for deriving sorbitan esters include, but are not limited to, fatty acids as described herein. Suitable sorbitan esters include, but are not limited to, the Span™ series (available from Uniqema), which includes Span 20 (sorbitan monolaurate), 40 (sorbitan monopalmitate), 60 ( Sorbitan monostearate), 65 (sorbitan tristearate), 80 (sorbitan monooleate), and 85 (sorbitan trioleate). Other suitable sorbitan esters include R.I. C. Rowe and P.M. J. Includes those listed in Shesky, Handbook of Pharmaceutical Excipients, (2006), 5th Edition.
本明細書で使用するとき、「ポリエトキシル化ソルビタンエステル」という用語は、ソルビタンエステルのエトキシル化から誘導された化合物、または化合物の混合物を指す。この化合物のポリオキシエチレン部分は、脂肪エステルとソルビタン部分との間にあり得る。本明細書で使用するとき、「ソルビタンエステル」という用語は、ソルビトールと少なくとも1つの脂肪酸のエステル化から誘導された化合物、または化合物の混合物を指す。ポリエトキシル化ソルビタンエステルを誘導するために有用な脂肪酸としては、限定されるものではないが、本明細書で記載されるようなものが挙げられる。いくつかの実施形態では、化合物またはその混合物のポリオキシエチレン部分は、約2〜約200個のオキシエチレン単位を有する。いくつかの実施形態では、この化合物または混合物のポリオキシエチレン部分は、約2〜100個のオキシエチレン単位を有する。いくつかの実施形態では、この化合物または混合物のポリオキシエチレン部分は、約4〜80個のオキシエチレン単位を有する。いくつかの実施形態では、この化合物または混合物のポリオキシエチレン部分は、約4〜40個のオキシエチレン単位を有する。いくつかの実施形態では、この化合物または混合物のポリオキシエチレン部分は、約4〜20個のオキシエチレン単位を有する。好適なポリエトキシル化ソルビタンエステルとしては、限定されるものではないが、Tween(商標)シリーズ(Uniqemaから入手可能)が挙げられ、これは、Tween20(POE(20)ソルビタンモノラウレート)、21(POE(4)ソルビタンモノラウレート)、40(POE(20)ソルビタンモノパルミテート)、60(POE(20)ソルビタンモノステアレート)、60K(POE(20)ソルビタンモノステアレート)、61(POE(4)ソルビタンモノステアレート)、65(POE(20)ソルビタントリステアレート)、80(POE(20)ソルビタンモノオレエート)、80K(POE(20)ソルビタンモノオレエート)、81(POE(5)ソルビタンモノオレエート)、および85(POE(20)ソルビタントリオレエート)を含む。本明細書で使用するとき、略記「POE」とは、ポリオキシエチレンを指す。POE略記に続く数は、化合物中のオキシエチレン反復単位の数を指す。他の好適なポリエトキシル化ソルビタンエステルとしては、参照によりその全体を本明細書に組み込んだ、R.C.RoweおよびP.J.Shesky著,Handbook of pharmaceutical excipients,(2006年),第5版に記載されているポリオキシエチレンソルビタン脂肪酸エステルが挙げられる。いくつかの実施形態において、このポリエトキシル化ソルビタンエステルはポリソルベートである。いくつかの実施形態において、このポリエトキシル化ソルビタンエステルはポリソルベート20である。 As used herein, the term “polyethoxylated sorbitan ester” refers to a compound, or mixture of compounds, derived from the ethoxylation of a sorbitan ester. The polyoxyethylene portion of the compound can be between the fatty ester and sorbitan portion. As used herein, the term "sorbitan ester" refers to a compound, or mixture of compounds, derived from the esterification of sorbitol with at least one fatty acid. Fatty acids useful for deriving polyethoxylated sorbitan esters include, but are not limited to, those described herein. In some embodiments, the polyoxyethylene portion of the compound or mixture thereof has about 2 to about 200 oxyethylene units. In some embodiments, the polyoxyethylene portion of the compound or mixture has about 2-100 oxyethylene units. In some embodiments, the polyoxyethylene portion of the compound or mixture has about 4-80 oxyethylene units. In some embodiments, the polyoxyethylene portion of the compound or mixture has about 4-40 oxyethylene units. In some embodiments, the polyoxyethylene portion of the compound or mixture has about 4-20 oxyethylene units. Suitable polyethoxylated sorbitan esters include, but are not limited to, the Tween™ series (available from Uniqema), which includes Tween 20 (POE(20) sorbitan monolaurate), 21 ( POE (4) sorbitan monolaurate), 40 (POE (20) sorbitan monopalmitate), 60 (POE (20) sorbitan monostearate), 60K (POE (20) sorbitan monostearate), 61 (POE( 4) sorbitan monostearate), 65 (POE(20) sorbitan tristearate), 80 (POE(20) sorbitan monooleate), 80K (POE(20) sorbitan monooleate), 81 (POE(5) Sorbitan monooleate), and 85 (POE(20) sorbitan trioleate). As used herein, the abbreviation "POE" refers to polyoxyethylene. The number following the POE abbreviation refers to the number of oxyethylene repeat units in the compound. Other suitable polyethoxylated sorbitan esters include R.I. C. Rowe and P.M. J. The polyoxyethylene sorbitan fatty acid ester described in Shesky's Handbook of pharmaceutical excitants, (2006), 5th edition is mentioned. In some embodiments, the polyethoxylated sorbitan ester is polysorbate. In some embodiments, the polyethoxylated sorbitan ester is polysorbate 20.
本明細書で使用するとき、「グリセリル脂肪エステル」という用語は、脂肪酸のモノ−、ジ−、またはトリグリセリドを指す。グリセリル脂肪エステルは、必要に応じて、スルホン酸基、またはその医薬上許容される塩で置換されてよい。脂肪酸のグリセリドを誘導するための好適な脂肪酸としては、限定されるものではないが、本明細書に記載されるものが挙げられる。いくつかの実施形態では、グリセリル脂肪エステルは、12〜18個の炭素原子を有する脂肪酸のモノ−グリセリドである。いくつかの実施形態では、このグリセリル脂肪エステルはグリセリルステアレートである。 As used herein, the term "glyceryl fatty ester" refers to fatty acid mono-, di-, or triglycerides. The glyceryl fatty ester may be optionally substituted with a sulfonic acid group, or a pharmaceutically acceptable salt thereof. Suitable fatty acids for deriving fatty acid glycerides include, but are not limited to, those described herein. In some embodiments, the glyceryl fatty ester is a mono-glyceride of a fatty acid having 12-18 carbon atoms. In some embodiments, the glyceryl fatty ester is glyceryl stearate.
本明細書で使用するとき、「トリグリセリド」という用語は、脂肪酸のトリグリセリドを指す。いくつかの実施形態では、このトリグリセリドは中鎖トリグリセリドである。 As used herein, the term “triglyceride” refers to triglycerides of fatty acids. In some embodiments, the triglyceride is a medium chain triglyceride.
本明細書で使用するとき、「アルキレングリコール」という用語は、式−O−アルキレン−の基を指し、式中、アルキレン基は、2〜6個、2〜4個、または2〜3個の炭素原子を有する。いくつかの実施形態では、このアルキレングリコールは、プロピレングリコール(1,2−プロパンジオール)である。 As used herein, the term "alkylene glycol" refers to a group of formula -O-alkylene-, where the alkylene group is 2-6, 2-4, or 2-3. It has a carbon atom. In some embodiments, the alkylene glycol is propylene glycol (1,2-propanediol).
本明細書で使用するとき、「ポリエチレングリコール」という用語は、式−O−CH2−CH2−のエチレングリコールモノマー単位を含有するポリマーを指す。好適なポリエチレングリコールは、ポリマー分子の各末端で遊離ヒドロキシル基を有し得るか、または例えばメチル基のような低級アルキルでエーテル化された1つ以上のヒドロキシル基を有し得る。更に好適なものは、エステル化可能なカルボキシ基を有するポリエチレングリコールの誘導体である。本発明で有用なポリエチレングリコールは、任意の鎖長さまたは分子量のポリマーであり得、ならびに分岐を含み得る。いくつかの実施形態では、ポリエチレングリコールの平均分子量は、約200〜約9000である。いくつかの実施形態では、ポリエチレングリコールの平均分子量は、約200〜約5000である。いくつかの実施形態では、ポリエチレングリコールの平均分子量は、約200〜約900である。いくつかの実施形態では、ポリエチレングリコールの平均分子量は、約400である。好適なポリエチレングリコールとしては、ポリエチレングリコール−200、ポリエチレングリコール−300、ポリエチレングリコール−400、ポリエチレングリコール−600、およびポリエチレングリコール−900が挙げられるが、限定されるものではない。名称のダッシュに続く数字は、ポリマーの平均分子量を指す。 The term "polyethylene glycol" as used herein refers to a polymer containing ethylene glycol monomer units of the formula -O-CH2-CH2-. Suitable polyethylene glycols may have a free hydroxyl group at each end of the polymer molecule, or may have one or more hydroxyl groups etherified with a lower alkyl such as a methyl group. Even more preferred are derivatives of polyethylene glycol with esterifiable carboxy groups. Polyethylene glycols useful in the present invention can be polymers of any chain length or molecular weight, as well as containing branches. In some embodiments, polyethylene glycol has an average molecular weight of about 200 to about 9000. In some embodiments, the polyethylene glycol has an average molecular weight of about 200 to about 5000. In some embodiments, polyethylene glycol has an average molecular weight of about 200 to about 900. In some embodiments, the polyethylene glycol has an average molecular weight of about 400. Suitable polyethylene glycols include, but are not limited to, polyethylene glycol-200, polyethylene glycol-300, polyethylene glycol-400, polyethylene glycol-600, and polyethylene glycol-900. The number following the dash in the name refers to the average molecular weight of the polymer.
本発明のある特徴は、明確さのために別個の実施形態の説明の中で記載されているが、それは、1つの実施形態の説明の中で組合せで適用され得ることを更に理解されたい。逆に、本発明の様々な特徴が、簡潔さのため、1つの実施例の説明の中で記載されているが、それらは分けて、または適切な副組合せとして適用され得る。
方法
Although certain features of the invention are described in the description of separate embodiments for clarity, it should be further understood that they may be applied in combination within the description of one embodiment. Conversely, various features of the invention, which, for brevity, are described in the description of one embodiment, may be applied separately or as suitable subcombinations.
Method
本発明の医薬製剤は、皮膚障害の治療で有用である。いくつかの実施形態では、この皮膚障害は、尋常性天疱瘡(PV)または水疱性類天疱瘡(BP)のような自己免疫水疱性皮膚疾患である。いくつかの実施形態では、この皮膚障害は、乾癬(例えば、尋常性乾癬)、アトピー性皮膚炎、皮疹、皮膚刺激性、皮膚感作(例えば、接触性皮膚炎またはアレルギー性接触性皮膚炎)である。例えば、いくつかの薬剤を含むある物質が、局所的に適用される場合、皮膚感作を生じる場合がある。いくつかの実施形態では、望ましくない感作を生じる薬剤と一緒に本発明の局所製剤の共投与または逐次的投与することは、このような望ましくない感作または皮膚炎を治療する上で有用であり得る。 The pharmaceutical formulations of the present invention are useful in treating skin disorders. In some embodiments, the skin disorder is an autoimmune bullous skin disease such as pemphigus vulgaris (PV) or bullous pemphigoid (BP). In some embodiments, the skin disorder is psoriasis (eg, psoriasis vulgaris), atopic dermatitis, rash, skin irritation, skin sensitization (eg, contact dermatitis or allergic contact dermatitis). Is. For example, certain substances, including some drugs, may cause skin sensitization when applied topically. In some embodiments, co-administration or sequential administration of the topical formulations of the present invention with agents that cause undesired sensitization is useful in treating such undesired sensitization or dermatitis. possible.
本発明は、本発明の化合物の投与による他の医薬品の皮膚医学的副作用を治療する方法を更に提供する。例えば、多くの医薬品が、ざ瘡様発疹または関連する皮膚炎として顕症し得る望ましくないアレルギー反応をもたらすことがある。このような望ましくない副作用を有する医薬品の例としては、ゲフィチニブ、セツキマブ、エルロチニブ等の抗癌剤が挙げられる。本発明の製剤は、望ましくない皮膚医学的副作用を有する医薬品と組み合わせて(同時にまたは逐次的に)全身または局所的に投与することができる。いくつかの実施形態では、本発明の製剤の不在下で局所的に適用される場合、接触性皮膚炎、アレルギー性接触性皮膚炎、または同様な皮膚障害を発症するような他の医薬品の1つ以上と一緒に本発明の製剤を投与することができる。したがって、本発明の製剤は、皮膚炎、皮膚障害、または関連する副作用を起こし得る追加的な医薬品を更に含んでいる局所的製剤を包含する。 The present invention further provides methods of treating the dermatological side effects of other pharmaceuticals by administering the compounds of the present invention. For example, many medications can lead to unwanted allergic reactions that can manifest as acne-like rashes or associated dermatitis. Examples of drugs having such undesirable side effects include anticancer agents such as gefitinib, cetuximab, erlotinib. The formulations of the present invention may be administered systemically or locally (simultaneously or sequentially) in combination with a drug having undesirable dermatological side effects. In some embodiments, one of the other medicinal products that develops contact dermatitis, allergic contact dermatitis, or similar skin disorders when applied topically in the absence of a formulation of the invention. The formulations of the invention can be administered with one or more. Thus, the formulations of the present invention include topical formulations that further include additional pharmaceutical agents that may cause dermatitis, skin disorders, or related side effects.
本明細書で使用するとき、「個体」または「患者」という用語は互換的に用いられ、哺乳類、好ましくはマウス、ラット、他の囓歯類、ウサギ、イヌ、ネコ、ブタ、ウシ、ヒツジ、ウマ、または霊長類、ならびに最も好ましくはヒトを含む任意の動物を指す。 As used herein, the terms "individual" or "patient" are used interchangeably and refer to mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, Refers to any animal, including horses, or primates, and most preferably humans.
本明細書で使用するとき、「治療的に有効な量」という表現は、研究者、獣医師、医師または他の臨床医が求める、組織、系、動物、個体またはヒトにおける生物学的応答または医学的応答を誘発する活性化合物または医薬品の量を指す。 As used herein, the expression "therapeutically effective amount" refers to a biological response in a tissue, system, animal, individual or human that a researcher, veterinarian, doctor or other clinician seeks. Refers to the amount of active compound or pharmaceutical agent that elicits a medical response.
本明細書で使用するとき、「治療する、treating」または「治療、treatment」という用語は、(1)疾患を予防すること;例えば疾患、病状または異常の素因を呈し得るが、その疾患の病態または症状を未だ経験或いは発症してはいない個体において、疾患、病状または異常を防止すること、(2)疾患を阻害すること;例えば、疾患、病状または異常の病態もしくは症状を経験或いは発症している個体において、疾患、病状または異常を阻害すること(すなわち、病態および/または症状の更なる進行を阻止すること)、ならびに(3)疾患を軽減すること;例えば、例えば、疾患の重篤度を低減させるように、疾患、病状または異常の病態もしくは症状を経験或いは発症している固体において、疾患、病状または異常を軽減すること(すなわち、病態および/または症状を逆転させること)のうちの1つ以上を指す。 As used herein, the term "treating," or "treatment, treatment" refers to (1) preventing a disease; eg, predisposing to a disease, condition or abnormality, but the pathology of that disease. Or preventing a disease, condition or abnormality in an individual who has not yet experienced or developed the condition, (2) inhibiting the disease; for example, having experienced or developed the condition or condition of the disease, the condition or the abnormality. In a living individual, inhibiting a disease, condition or abnormality (ie, preventing further progression of the condition and/or symptoms), and (3) alleviating the disease; eg, severity of the disease, for example. Ameliorating a disease, condition or abnormality in an individual who is experiencing or developing the condition or condition of the disease, condition or abnormality (ie reversing the condition and/or symptoms). Refers to one or more.
併用療法
例えば化学療法剤、抗炎症剤、ステロイド、免疫抑制剤、ならびに国際特許公開第WO2006/056399号に記載されているもののようなBcr−Abl、Flt−3、RAFおよびFAKキナーゼ阻害剤、または他の薬剤のような1つ以上の追加的医薬品が、JAK関連疾患、障害または病状の治療のために、本発明の製剤と併用して使用され得る。これらの追加的医薬品の1つ以上は、同時にまたは逐次的に患者に投与することができる。
Combination therapies, such as chemotherapeutic agents, anti-inflammatory agents, steroids, immunosuppressive agents, and Bcr-Abl, Flt-3, RAF and FAK kinase inhibitors, such as those described in International Patent Publication No. WO 2006/056399, or One or more additional pharmaceutical agents, such as other agents, can be used in combination with the formulations of the invention for the treatment of JAK-related diseases, disorders or conditions. One or more of these additional pharmaceutical agents can be administered to the patient simultaneously or sequentially.
化学療法剤の例としては、プロテオソーム阻害剤(例えば、ボルテゾミブ)、サリドマイド、レブリミド、およびメルファラン、ドキソルビシン、シクロホスファミド、ビンクリスチン、エトポシド、カルムスチン等のようなDNA損傷剤が挙げられる。 Examples of chemotherapeutic agents include proteosome inhibitors (eg, bortezomib), thalidomide, levulimide, and DNA damaging agents such as melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide, carmustine and the like.
ステロイドの例としては、デキサメタゾンまたはプレドニゾンのようなコルチコステロイドが挙げられる。 Examples of steroids include corticosteroids such as dexamethasone or prednisone.
Bcr−Ab1阻害剤の例としては、米国特許第5,521,184号、国際特許公開第WO04/005281号、および米国特許出願第60/578,491号に開示されている属および種の化合物、およびそれらの薬学的に供用可能な塩が挙げられる。 Examples of Bcr-Abl inhibitors include compounds of the genera and species disclosed in U.S. Patent No. 5,521,184, International Patent Publication No. WO 04/005281, and U.S. Patent Application No. 60/578,491. , And pharmaceutically acceptable salts thereof.
好適なFlt−3阻害剤の例としては、国際特許公開第WO03/037347号、同第03/099771号、および同第04/046120号に開示されているような化合物、およびそれらの医薬上許容される塩が挙げられる。 Examples of suitable Flt-3 inhibitors include compounds such as those disclosed in International Patent Publication Nos. WO03/037347, 03/099771, and 04/046120, and their pharmaceutically acceptable compounds. Examples of the salts include:
好適なRAF阻害剤の例としては、国際特許公開第WO00/09495号および同第WO05/028444号に開示されているような化合物、およびそれらの医薬上許容される塩が挙げられる。 Examples of suitable RAF inhibitors include compounds as disclosed in WO 00/09495 and WO 05/028444, and pharmaceutically acceptable salts thereof.
好適なFAK阻害剤の例としては、国際特許公開第WO04/080980号、同第WO04/056786号、同第WO03/024967号、同第WO01/064655号、同第WO00/053595号、および同第WO01/014402号に開示されているような化合物、およびそれらの医薬上許容される塩が挙げられる。 Examples of suitable FAK inhibitors include International Patent Publication Nos. WO04/080980, WO04/056786, WO03/024967, WO01/064655, WO00/053595, and WO00/053595. Mention may be made of compounds such as those disclosed in WO 01/014402, and their pharmaceutically acceptable salts.
いくつかの実施形態では、本発明の製剤は、特にイマチニブまたは他のキナーゼ阻害剤に耐性を有する患者を治療するために、イマチニブを含む1つ以上のキナーゼ阻害剤と併用されて使用され得る。 In some embodiments, the formulations of the present invention may be used in combination with one or more kinase inhibitors including imatinib, particularly to treat patients who are resistant to imatinib or other kinase inhibitors.
いくつかの実施形態では、デキサメタゾンのようなコルチコステロイドが、本発明の化合物と併用されて患者に投与され、ここでは、デキサメタゾンが連続的ではなく断続的に投与される。 In some embodiments, a corticosteroid such as dexamethasone is administered to a patient in combination with a compound of the invention where dexamethasone is administered intermittently rather than continuously.
標識化合物およびアッセイ法
本発明の別の態様は、ヒトを含める組織試料中でのJAKを局在化させかつ定量するために、ならびに標識化合物の結合を阻害することによって、JAKリガンドを同定するために、画像撮影技術だけではなく、インビトロおよびインビボの双方におけるアッセイでも有用であると考えられる標識活性化合物(放射標識、蛍光標識など)を含む製剤に関する。したがって、本発明は、このような標識化合物を含有するJAKアッセイを包含する。
Labeled Compounds and Assays Another aspect of the invention is to localize and quantify JAK in tissue samples, including humans, and to identify JAK ligands by inhibiting the binding of labeled compounds. In particular, it relates to formulations containing labeled active compounds (radiolabels, fluorescent labels, etc.) which are considered to be useful in both in vitro and in vivo assays as well as imaging techniques. Accordingly, the invention includes JAK assays containing such labeled compounds.
本発明は、同位元素により標識付けされた化合物の製剤を更に含む。「同位元素により標識付けされた」または「放射標識付けされた」化合物とは、自然界で典型的に見出される(すなわち自然発生の)原子質量または質量数とは異なる原子質量または質量数を有する原子によって、1つ以上の原子が交換または置換されているような化合物である。本発明の化合物に組み込まれる好適な放射核種としては、限定されるものではないが、2H(重水素(deuterium)を指すDとも表記される)、3H(三重水素(tritium)を指すTとも表記される)、11C、13C、14C、13N、15N、15O、17O、18O、18F、35S、36Cl、82Br、75Br、76Br、77Br、123I、124I、125Iおよび131Iが挙げられる。この放射標識化合物中に組み込まれる放射核種は、放射標識化合物の特定の用途に依存するだろう。例えば、インビトロでのJAK標識付けおよび競合アッセイのためには、3H、14C、82Br、125I、131I、または35Sを組み込む化合物が概ね最も有用でであろう。放射画像撮影用途については、11C、18F、125I、123I、124I、131I、75Br、76Brまたは77Brが概ね最も有用であろう。 The invention further includes formulations of isotope-labeled compounds. “Isotope-labeled” or “radio-labeled” compound refers to an atom having an atomic mass or mass number that differs from the atomic mass or mass number typically found in nature (ie, naturally occurring). Is a compound in which one or more atoms are replaced or substituted by. Suitable radionuclides to be incorporated into the compounds of the present invention include, but are not limited to, 2 H (also referred to as D for deuterium), 3 H (T for tritium). Also described), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 18 F, 35 S, 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br. , 123 I, 124 I, 125 I and 131 I. The radionuclide that is incorporated into the radiolabeled compound will depend on the particular application of the radiolabeled compound. For example, for in vitro JAK labeling and competition assays, compounds that incorporate < 3 >H, < 14 >C, < 82 >Br, <125> I, <131> I, or <35> S will generally be most useful. For radiographic applications, 11 C, 18 F, 125 I, 123 I, 124 I, 131 I, 75 Br, 76 Br or 77 Br will generally be most useful.
「放射標識化合物」または「標識化合物」は、少なくとも1つの放射核種を組み込んだ化合物である。いくつかの実施形態では、放射核種は、3H、14C、125I、35Sおよび82Brからなる群から選択される。 A "radiolabeled compound" or "labeled compound" is a compound that incorporates at least one radionuclide. In some embodiments, the radionuclide is selected from the group consisting of 3 H, 14 C, 125 I, 35 S and 82 Br.
キット
本発明はまた、例えば、癌のようなJAK関連疾患または異常の治療または予防で有用な薬剤学的キットを含み、これは本発明の医薬製剤を含有する1つ以上の容器を収容する。当業者には明らかなように、このようなキットは、所望の場合、例えば、1つ以上の薬剤的に許容可能な担体を有する容器、追加の容器などのような1つ以上の様々な従来の薬剤学キット要素を更に収容する。投与される成分の量、投与のガイドライン、および/または成分を混合するためのガイドラインを示す添付文書またはラベルのいずれかのような取扱説明書を、キット内に含めることもできる。
Kits The present invention also includes pharmaceutical kits useful, for example, in the treatment or prevention of JAK-related diseases or disorders such as cancer, which contain one or more containers containing a pharmaceutical formulation of the invention. As will be apparent to one of skill in the art, such kits may, if desired, comprise one or more of a variety of conventional reagents such as, for example, a container with one or more pharmaceutically acceptable carriers, additional containers, and the like. Further contains the pharmaceutical kit components of Instructions such as either a package insert or a label indicating the amount of ingredients to be administered, guidelines for administration, and/or guidelines for mixing the ingredients can also be included in the kit.
本発明は、特定の実施例によってより一層詳細に説明される。以下の実施例は、説明の目的で提供され、本発明の範囲をどのような形でも限定することを意図するものではない。変更または修正されて本質的に同一の結果を得ることができる、重要ではない種々のパラメータを当業者は容易に認識するであろう。いくつかの実施形態において、本発明は、例示的製剤(例えば実施例3)で特定される成分を含む医薬製剤を提供し、それらの成分は、おおよそ表2〜5で示された量で存在する。 The invention will be explained in more detail by means of specific examples. The following examples are provided for purposes of illustration and are not intended to limit the scope of the invention in any way. Those of ordinary skill in the art will readily recognize a variety of non-critical parameters that may be altered or modified to obtain essentially the same results. In some embodiments, the present invention provides pharmaceutical formulations that include the components identified in the exemplary formulations (eg, Example 3), which components are present in amounts approximately shown in Tables 2-5. To do.
実施例1:(3R)−および(3S)−3−シクロペンチル−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]プロパンニトリル
ステップ1.(2E)−および(2Z)−3−シクロペンチルアクリロニトリル
THF(235mL)中の1.0Mのカリウムtert−ブトキシドの溶液に、THF(300mL)中のジエチルシアノメチルホスフェート(39.9mL、0.246モル)の溶液を0℃で滴下で添加した。冷浴を除去し、反応物を室温まで温め、次いで0℃に再冷却し、この時点で、THF(60mL)中のシクロペンタンカルバルデヒド(22.0g、0.224モル)の溶液を滴下で添加した。水浴を除去し、反応物を周辺温度まで温め、64時間攪拌した。混合物をジエチルエーテルと水とに分配し、水相をエーテルで三回抽出し、続いて酢酸エチルで二回抽出した。合わせた抽出液をブラインで洗浄し、次いで硫酸ナトリウム上で乾燥させ、濾過し、真空中で濃縮し、オレフィン異性体24.4gを含有する混合物を得、これを更に精製することなく使用した(89%)。
1H NMR(400MHz、CDCl3):δ6.69(dd,1H、トランスオレフィン)、6.37(t,1H、シスオレフィン)、5.29(dd,1H、トランスオレフィン)、5.20(d,1H、シスオレフィン)、3.07−2.95(m,1H、シス生成物)、2.64−2.52(m,1H、トランス生成物)、1.98−1.26(m、16H)。
Step 1. (2E)- and (2Z)-3-Cyclopentylacrylonitrile To a solution of 1.0 M potassium tert-butoxide in THF (235 mL) was added diethyl cyanomethyl phosphate (39.9 mL, 0.246 mol) in THF (300 mL). ) Was added dropwise at 0°C. The cold bath was removed and the reaction was allowed to warm to room temperature then recooled to 0° C. at which point a solution of cyclopentanecarbaldehyde (22.0 g, 0.224 mol) in THF (60 mL) was added dropwise. Was added. The water bath was removed and the reaction was warmed to ambient temperature and stirred for 64 hours. The mixture was partitioned between diethyl ether and water, the aqueous phase was extracted three times with ether and then twice with ethyl acetate. The combined extracts were washed with brine then dried over sodium sulphate, filtered and concentrated in vacuo to give a mixture containing 24.4 g of the olefin isomer, which was used without further purification ( 89%).
1 H NMR (400 MHz, CDCl 3 ): δ 6.69 (dd, 1 H, trans olefin), 6.37 (t, 1 H, cis olefin), 5.29 (dd, 1 H, trans olefin), 5.20 ( d,1H, cis-olefin), 3.07-2.95 (m, 1H, cis product), 2.64-2.52 (m, 1H, trans product), 1.98-1.26( m, 16H).
ステップ2:(3R)−および(3S)−3−シクロペンチル−3−[4−(7−[2−(トリメチルシリル)エトキシ]メチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]プロパンニトリル
ACN(300mL)中の4−(1H−ピラゾール−4−イル)−7−[2−(トリメチルシリル)エトキシ]メチル−7H−ピロロ[2,3−d]ピリミジン(15.0g、0.0476モル)の溶液に、3−シクロペンチルアクリロニトリル(15g、0.12モル)(シスおよびトランス異性体の混合物として)を添加し、続いてDBU(15mL、0.10モル)を添加した。得られた混合物を室温で一夜攪拌した。ACNを蒸発させた。混合物を、酢酸エチルで希釈し、溶液を1.0NのHClで洗浄した。水相を酢酸エチルで三回、逆抽出した。合わせた有機相をブラインで洗浄し、硫酸ナトリウム上で乾燥させ、濾過し、濃縮した。粗生成物をシリカゲルクロマトグラフィー(酢酸エチル/ヘキサンの濃度勾配)で精製し、粘性透明シロップを得て、これをエタノール中に溶解し、数回蒸発させて酢酸エチルを除去し、19.4gのラセミ体付加物を得た(93%)。エナンチオマーを分取HPLCによって分離し(OD−H、15%エタノール/ヘキサン)、これらの対応する最終生成物を生成するために、これらを次のステップで別個に使用した。それぞれの分離されたエナンチオマーから生じている最終生成物(工程3参照)は、活性JAK阻害剤として認められたが、分取HPLCから溶出した第2ピークから生じる最終生成物は、そのエナンチオマーよりも一層活性であった。
1H NMR(300MHz、CDCl3):δ8.85(s、1H)、8.32(s,2H)、7.39(d、1H)、6.80(d,1H)、5.68(s,2H)、4.26(dt,1H)、3.54(t,2H)、3.14(dd,1H)、2.95(dd,1H)、2.67−2.50(m,1H)、2.03−1.88(m,1H)、1.80−1.15(m,7H)、0.92(t,2H)、−0.06(s,9H);MS(ES):437(M+1)。
ステップ3:(3R)−および(3S)−3−シクロペンチル−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]プロパンニトリル
Step 2: (3R)- and (3S)-3-cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl). -1H-pyrazol-1-yl]propanenitrile 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d in ACN (300 mL). ] To a solution of pyrimidine (15.0 g, 0.0476 mol) was added 3-cyclopentylacrylonitrile (15 g, 0.12 mol) (as a mixture of cis and trans isomers), followed by DBU (15 mL, 0. 10 mol) was added. The resulting mixture was stirred at room temperature overnight. The ACN was evaporated. The mixture was diluted with ethyl acetate and the solution washed with 1.0 N HCl. The aqueous phase was back extracted three times with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulphate, filtered and concentrated. The crude product was purified by silica gel chromatography (ethyl acetate/hexane gradient) to give a viscous clear syrup, which was dissolved in ethanol and evaporated several times to remove ethyl acetate and 19.4 g. A racemic adduct was obtained (93%). The enantiomers were separated by preparative HPLC (OD-H, 15% ethanol/hexane) and these were used separately in the next step to produce their corresponding final products. The final product resulting from each separated enantiomer (see step 3) was recognized as an active JAK inhibitor, but the final product resulting from the second peak eluting from preparative HPLC was more than the enantiomer. It was more active.
1 H NMR (300 MHz, CDCl 3 ): δ 8.85 (s, 1H), 8.32 (s, 2H), 7.39 (d, 1H), 6.80 (d, 1H), 5.68 ( s, 2H), 4.26 (dt, 1H), 3.54 (t, 2H), 3.14 (dd, 1H), 2.95 (dd, 1H), 2.67-2.50 (m. , 1H), 2.03-1.88 (m, 1H), 1.80-1.15 (m, 7H), 0.92 (t, 2H), -0.06 (s, 9H); MS. (ES): 437 (M+1).
Step 3: (3R)- and (3S)-3-Cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile
DCM(40mL)中の3−シクロペンチル−3−[4−(7−[2−(トリメチルシリル)エトキシ]メチル−7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]プロパンニトリル(6.5g、0.015モル、上記のように単離されたRまたはSエナンチオマー)の溶液に、TFA(16mL)を添加し、これを6時間攪拌した。溶媒およびTFAを真空中で除去した。残渣をDCM中に溶解し、ロータリーエバポレーターを使用して濃縮し、これを更に二回繰り返し、TFAを可能な限り除去した。これに続いて、残渣をメタノール(30mL)中のエチレンジアミン(4mL、0.06モル)中で一夜攪拌した。真空中で溶媒を除去し、水を添加し、生成物を酢酸エチルで三回抽出した。合わせた抽出物をブラインで洗浄し、硫酸ナトリウム上で乾燥させて、デカントし、濃縮して粗生成物を得て、これをフラッシュカラムクロマトグラフィー(メタノール/DCMの濃度勾配で溶出)によって精製した。得られた混合物を、分取−HPLC/MS(0.15%NH4OHを含有するACN/H2Oの濃度勾配で溶出するC18)で更に精製し、生成物(2.68g、58%)を得た。
1H NMR(400MHz、D6−dmso):δ12.11(brs、1H)、8.80(s、1H)、8.67(s,1H)、8.37(s、1H)、7.60(d、1H)、6.98(d,1H)、4.53(dt,1H)、3.27(dd,1H)、3.19(dd,1H)、2.48−2.36(m,1H)、1.86−1.76(m,1H)、1.68−1.13(m,7H);MS(ES):307(M+1)。
3-Cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole-1 in DCM (40 mL). To a solution of -yl]propanenitrile (6.5 g, 0.015 mol, R or S enantiomer isolated as above) was added TFA (16 mL) and this was stirred for 6 hours. The solvent and TFA were removed in vacuo. The residue was dissolved in DCM and concentrated using a rotary evaporator, which was repeated twice more to remove TFA as much as possible. Following this, the residue was stirred in ethylenediamine (4 mL, 0.06 mol) in methanol (30 mL) overnight. The solvent was removed in vacuo, water was added and the product was extracted with ethyl acetate three times. The combined extracts were washed with brine, dried over sodium sulfate, decanted and concentrated to give a crude product which was purified by flash column chromatography (eluting with a methanol/DCM gradient). .. The resulting mixture was further purified by preparative -HPLC / MS (C18 eluting with a gradient of ACN / H 2 O containing 0.15% NH 4 OH), the product (2.68 g, 58% ) Got.
1 H NMR (400 MHz, D 6 -dmso): δ 12.11 (brs, 1H), 8.80 (s, 1H), 8.67 (s, 1H), 8.37 (s, 1H), 7. 60 (d, 1H), 6.98 (d, 1H), 4.53 (dt, 1H), 3.27 (dd, 1H), 3.19 (dd, 1H), 2.48-2.36. (M, 1H), 1.86-1.76 (m, 1H), 1.68-1.13 (m, 7H); MS (ES): 307 (M+1).
実施例2:(R)−3−(4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル)−3−シクロペンチルプロパンニトリルのリン酸塩
このリン酸塩は、1H NMRによって、1:1塩であることが示され、結晶化度がX線粉末回折(XRPD)によって確認された。示差走査熱量測定(DSC)は、約198.66℃で鋭い溶融ピークをもたらした。この生成物は、TGAにより、200℃まで重量損失がほとんどないことを示した。 The phosphate was shown to be a 1:1 salt by 1 H NMR and the crystallinity was confirmed by X-ray powder diffraction (XRPD). Differential scanning calorimetry (DSC) gave a sharp melting peak at about 198.66°C. The product showed by TGA almost no weight loss up to 200°C.
実施例3:(R)−3−(4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル)−3−シクロペンチルプロパンニトリルリン酸塩の水中油クリーム製剤の調製
水中油クリーム製剤を、(R)−3−(4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル)−3−シクロペンチルプロパンニトリルリン酸塩(実施例2)について、製剤(遊離塩基等価物)の0.5重量%、1.0重量%および1.5重量%で調製した。15gのチューブのための組成が、以下の表2に提供される。3種の強度の製剤は、活性成分の量に基づいた精製水量に対する調整を除けば、同一であった。製剤で使用された全ての賦形剤は、公定グレード(すなわち、USP/NFまたはBP)もしくは局所的製品での使用が承認されたものである。
Example 3: (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate in water. Preparation of Oil Cream Formulation An oil-in-water cream formulation was prepared using (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentyl. Prepared for propanenitrile phosphate (Example 2) at 0.5%, 1.0% and 1.5% by weight of the formulation (free base equivalent). The composition for the 15 g tube is provided in Table 2 below. The three strength formulations were identical except for adjustments to the amount of purified water based on the amount of active ingredient. All excipients used in the formulations are official grade (ie USP/NF or BP) or approved for use in topical products.
0.5、1.0および1.5%での実施例2に関するクリーム製剤の典型的400kgバッチについての製剤処方がまた、それぞれ表3、4、および5に提供される。 Formulation formulations for a typical 400 kg batch of cream formulation for Example 2 at 0.5, 1.0 and 1.5% are also provided in Tables 3, 4, and 5, respectively.
ン−4−イル)−1H−ピラゾール−1−イル)−3−シクロペンチルプロパンニトリル
遊離塩基の1.0%と等価である。
水中油クリーム製剤は、3.5kgまたは400kg規模のいずれかで、以下の手順に従って合成された(3.5kgバッチサイズで製造される場合、表3〜5の量は適切に規模が下げられた)。若干のバッチが、混合容器およびミキサーのサイズのような、規模拡大に関連する小さな変更を受けた。一般的に、高せん断および低せん断ブレードを備えるオーバーヘッドミキサーが、このプロセスには好適である。図1は、水中油製剤を製造するためのプロセスのフローチャート表示である。(R)−3−(4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル)−3−シクロペンチルプロパンニトリルは、この適用の全体を通して「API」と称される。 Oil-in-water cream formulations were synthesized according to the following procedure, either on a 3.5 kg or 400 kg scale (when produced in a 3.5 kg batch size, the amounts in Tables 3-5 were scaled down appropriately. ). Some batches have undergone minor changes related to scaling, such as the size of the mixing vessel and mixer. Overhead mixers with high and low shear blades are generally suitable for this process. FIG. 1 is a flow chart representation of a process for producing an oil-in-water formulation. (R)-3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile is used throughout the application of the “API It is called.
手順
1.メチルパラベンとプロピルパラベンをプロピレングリコールの一部と混合することによって、パラベン相を調製した(表2〜5の%を参照)。
2.次に、キサンタンガムをプロピレングリコールと混合することによって、キサンタンガム相を調製した(表2〜5の%を参照)。
3.次いで、軽質鉱油、グリセリルステアレート、ポリソルベート20、白色ワセリン、セチルアルコール、ステアリルアルコール、ジメチコーンおよび中鎖トリグリセリドを混合することによって、油相を調製した。この相を70〜80℃に加熱して溶融させ、均一な混合物を形成させる。
4.次に、精製水、ポリエチレングリコール、および二ナトリウムEDTAを混合することによって、水相を調製した。この相を70〜80℃に加熱する。
5.ステップ4の水相、ステップ1のパラベン相、および実施例2(APIのリン酸塩)を合わせて、混合物を形成した。
6.次いで、ステップ2からのキサンタンガム相を、ステップ5からの混合物に添加した。
7.次いで、ステップ3からの油相を、高せん断混合下で、ステップ6からの混合物と合わせて、エマルジョンを形成した。
8.次いで、フェノキシエタノールをステップ7からのエマルジョンに添加した。混合を継続し、次いで低せん断下で、生成物を冷却した。
Procedure 1. The paraben phase was prepared by mixing methylparaben and propylparaben with a portion of propylene glycol (see% in Tables 2-5).
2. The xanthan gum phase was then prepared by mixing the xanthan gum with propylene glycol (see% in Tables 2-5).
3. The oil phase was then prepared by mixing light mineral oil, glyceryl stearate, polysorbate 20, white petrolatum, cetyl alcohol, stearyl alcohol, dimethicone and medium chain triglycerides. This phase is heated to 70-80° C. to melt and form a uniform mixture.
4. The aqueous phase was then prepared by mixing purified water, polyethylene glycol, and disodium EDTA. This phase is heated to 70-80°C.
5. The aqueous phase of Step 4, the paraben phase of Step 1, and Example 2 (API phosphate) were combined to form a mixture.
6. The xanthan gum phase from step 2 was then added to the mixture from step 5.
7. The oil phase from step 3 was then combined with the mixture from step 6 under high shear mixing to form an emulsion.
8. Phenoxyethanol was then added to the emulsion from step 7. Mixing was continued, then the product was cooled under low shear.
より大きな規模(例えば140kg)でのより均一なバッチは、実施例2を水相に徐々に添加し、次いで他の相と合わせることによって達成され得る。同様に、よりゆっくりとした冷却によって、より均一なバッチが達成され得る(例えば、低温の水よりはむしろ、反応器の外側ジャケット内の室温の水を使用することによって)。 A more uniform batch on a larger scale (eg 140 kg) can be achieved by gradually adding Example 2 to the aqueous phase and then combining with the other phases. Similarly, with slower cooling, a more uniform batch can be achieved (eg, by using room temperature water in the outer jacket of the reactor, rather than cold water).
クリーム製剤に関する分析結果および安定性試験
A.方法
クリームの外観を、視覚的に評価した。Brookfield粘度計を使用して、25℃にて粘度を測定した。最終クリーム製剤で、pHを測定した。微生物限度試験をUSPに従って実行した。チューブへのクリームの装填中に、充填重量を工程中試験として分析した。
Analytical results and stability studies on cream formulations A. Method The appearance of the cream was evaluated visually. Viscosity was measured at 25°C using a Brookfield viscometer. The pH was measured on the final cream formulation. Microbial limit testing was performed according to USP. The fill weight was analyzed as an in-process test during loading of the cream into the tube.
294nmでのUP検出を有する濃度勾配逆相HPLCによって、アッセイ、関連物質、素性および含量均一性が、製剤中で決定された。Waters社HPLCを、4Lの水への2mLのTFA(0.05%TFA)の移動相A、または4Lのメタノールへの2mLのTFA(0.05%TFA)の移動相Bを用いて、40℃の温度にて、1.0mL/分の流速で、Zorbax SB−C18カラム(3.5μm、4.6×150nm)と共に使用した。 Assays, related substances, identity and content homogeneity were determined in the formulations by gradient reverse phase HPLC with UP detection at 294 nm. Waters HPLC using 40 mL of mobile phase A with 2 mL TFA (0.05% TFA) in 4 L water or 2 mL TFA (0.05% TFA) in 4 L methanol 40 Used with a Zorbax SB-C18 column (3.5 μm, 4.6×150 nm) at a temperature of 0° C. and a flow rate of 1.0 mL/min.
B.結果
実施例2(遊離塩基を基準にした(API))の0.5%、1%および1.5%強度での3.5kgバッチについて、結果を以下に示す(表6)。
B. Results The results are shown below for 3.5 kg batches of Example 2 (API based on free base) at 0.5%, 1% and 1.5% strength (Table 6).
15gのアルミニウムチューブ内に貯蔵された、0.5、1.0および1.5%w/w強度でのクリーム製剤のバッチからの安定性データを、表7〜10および19〜20に提供する。更に琥珀色ガラス瓶(2オンス、テフロンキャップを有する)に封入された、0.5、1.0および1.5%w/w強度でのクリーム製剤のバッチからの安定性データを、表13〜17に提供し、一方、16オンスの琥珀色ガラス瓶に封入された、1.0%w/w製剤についてのより長期間の安定性データを、表11〜12に示す。医薬製剤に関する予備安定性データは、いずれの封入形態においても25℃/60%RHおよび40℃/75%RHで3ヶ月貯蔵後に、いかなる化学的不安定性も示さなかった。粘度の変化が、琥珀色のガラス瓶に貯蔵された製剤について、40℃/75%RHでの3ヶ月間の貯蔵後に認められた。しかしながら、医薬製剤の物理的評価は、いかなる相分離も示さなかった。許容基準が以下に示されている。 Stability data from batches of cream formulations at 0.5, 1.0 and 1.5% w/w strength stored in 15 g aluminum tubes are provided in Tables 7-10 and 19-20. .. Further stability data from batches of cream formulations at 0.5, 1.0 and 1.5% w/w strength, enclosed in amber glass bottles (2 ounces, with Teflon cap), are given in Table 13- Longer-term stability data for the 1.0% w/w formulation provided in 17 while enclosed in a 16 ounce amber glass bottle are shown in Tables 11-12. Pre-stability data for pharmaceutical formulations did not show any chemical instability after storage for 3 months at 25°C/60%RH and 40°C/75%RH in either encapsulated form. A change in viscosity was observed for the formulations stored in amber glass bottles after 3 months storage at 40°C/75%RH. However, physical evaluation of the pharmaceutical formulation did not show any phase separation. The acceptance criteria are shown below.
実施例4:溶解度試験
(R)−3−(4−7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル)−3−シクロペンチルプロパンニトリル(遊離塩基)またはそのリン酸塩の溶解度を決定するために、可能性のある溶媒の約5mLを、APIまたはその塩の約50mgに室温で添加した。混合物を懸濁させて、ホイール上で回転させた。混合物が透明な溶液になった場合、より多くの固体物質を添加した。懸濁液を24時間にわたって懸濁させた。試料を0.2マイクロメートルのフィルターを通して濾過した。液体部分を回収し、50/50水メタノール/水で希釈した。希釈した試料の濃度を、HPLCによって分析した。遊離塩基または塩がかなり不溶性である場合、結果はおおよその値のみである。
Example 4: Solubility test (R)-3-(4-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile (free base). Alternatively, to determine the solubility of its phosphate salt, about 5 mL of potential solvent was added to about 50 mg of API or its salt at room temperature. The mixture was suspended and spun on a wheel. More solid material was added when the mixture became a clear solution. The suspension was suspended for 24 hours. The sample was filtered through a 0.2 micrometer filter. The liquid portion was collected and diluted with 50/50 water methanol/water. The concentration of diluted sample was analyzed by HPLC. If the free base or salt is fairly insoluble, the results are only approximate values.
実施例5:他の局所製剤
(R)−3−(4−7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル)−3−シクロペンチルプロパンニトリルのリン酸塩を組み込む3種の異なる局所製剤を更に調製した。1%w/w分散クリーム(油中水製剤)、1%w/w無水軟膏、および1%w/wローションの組成が、表22に概要が示される(パーセンテージは遊離塩基を基準にしている)。APIのリン酸塩の1%w/wを有する各製剤は、プラセボと比較して粘度が低かった(プラセボでは、バランスは水である)。いかなる特定の理論に束縛されることを望まないが、より低い粘度は、リン酸塩の電解性質によるものであると考えられる。製剤およびプラセボの経時的な粘度は、表23に示される。1%分散クリーム(油中水製剤)は、40℃にての時効処理の2週間および4週間後に、離液現象を示したが、一方1%ローションおよび1%可溶化クリーム製剤(水中油製剤)は、離液現象を示さなかった。1%可溶化クリーム製剤は、1%ローションよりも概ねより高い粘度であった。
Example 5: Other Topical Formulations (R)-3-(4-7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile Phosphorus Three different topical formulations incorporating acid salts were also prepared. The composition of 1% w/w dispersion cream (water-in-oil formulation), 1% w/w anhydrous ointment, and 1% w/w lotion is summarized in Table 22 (percentages are based on free base). ). Each formulation with 1% w/w of API phosphate had a lower viscosity compared to placebo (where the balance is water). Without wishing to be bound by any particular theory, it is believed that the lower viscosity is due to the electrolytic nature of the phosphate. The formulations and placebo viscosities over time are shown in Table 23. 1% dispersion cream (water-in-oil formulation) showed syneresis after 2 and 4 weeks of aging treatment at 40°C, while 1% lotion and 1% solubilized cream formulation (oil-in-water formulation). ) Showed no syneresis. The 1% solubilized cream formulation was approximately higher in viscosity than the 1% lotion.
実施例6:皮膚透過性試験
実施例5(表20)の3種の異なる局所製剤および実施例3(表4)のクリーム製剤を、ヒトの死体皮膚の横断輸送について評価した。皮膚透過性データが表24に概要が示される。それぞれの製剤に関して、3つの反復試験中の輸送で、著しい変動が観察された。輸送における変動は、皮膚試料の差に一部は起因する可能性がある(ドナー、身体の領域、厚さ等)。概して、2種のクリーム製剤は、ローションまたは軟膏に比べてより高いフラックスを示した。軟膏製剤に関する輸送されたAPIの累加量は、他の3種の製剤と比較すると特に低く、これは、少なくとも部分的には、もたらす軟膏の不良な塗布性で、減少した輸送のための表面積がもたらされたことに起因する可能性がある。結果的として、2種のクリーム製剤が更なる開発のために選択され、1つは水中油系(上記実施例3を参照)として、他方は油中水エマルジョン系として選択された。薬剤物質の溶解度に基づいて、(R)−3−(4−7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル)−3−シクロペンチルプロパンニトリルリン酸塩の1.0、1.5、および2.0%w/wを含有する強度が、水中油系クリーム(可溶化クリーム)のために開発され、ならびに1.0、2.0、および3.0%w/wの強度が、油中水系クリーム(分散クリーム)のために開発された。皮膚透過性試験の手順は、以下に記載される。
Example 6: Skin Permeability Study The three different topical formulations of Example 5 (Table 20) and the cream formulation of Example 3 (Table 4) were evaluated for transdermal transport of human cadaver skin. The skin permeability data is summarized in Table 24. Significant variability was observed in the transport during the three replicates for each formulation. Variations in transport may be due, in part, to differences in skin samples (donor, body area, thickness, etc.). Overall, the two cream formulations showed higher flux compared to lotions or ointments. The cumulative loading API delivered for ointment formulations was particularly low when compared to the other three formulations, which was due, at least in part, to the poor application of the ointment resulting in reduced surface area for delivery. It may be due to what was brought. Consequently, two cream formulations were selected for further development, one as an oil-in-water system (see Example 3 above) and the other as a water-in-oil emulsion system. Based on the solubility of the drug substance, (R)-3-(4-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate Strengths containing 1.0, 1.5, and 2.0% w/w of salt were developed for oil-in-water creams (solubilized creams) and 1.0, 2.0, and 3 A strength of 0.0% w/w was developed for a water-in-oil cream (dispersion cream). The procedure of the skin permeability test is described below.
ヒトの死体皮膚輸送試験
局所製剤中のAPIの透過性を、ヒトの死体皮膚試料およびFranz拡散セルを用いて試験した。皮膚分節化ヒト死体皮膚は、組織バンクから入手され、一方Franz拡散セルは特注された。ドナーコンパートメントと受容コンパートメントとの間に適合するようサイズ合わせされたヒト死体皮膚試料を、Franz拡散セル上に配置させた。局所製剤を重量計測し(20mg)グラシン紙上に置き、製剤側を皮膚に向かって配置させて、しっかりと固定した。投与チャンバーをパラフィンで覆った。4%アルブミンを含有する生理食塩水で液だめ側を充填した。液だめを攪拌し、ドライブロック型ヒーターを使用して、37℃に維持した(Aungst B.著,Fatty Acid Skin Penetration Enhancers.Pharm.Res.1989年;6(3):244〜247頁)。4時間後に、1mLの試料を取り出し、生理食塩水+4%アルブミンの1mLで置き換えた。24時間後に、液だめ全体を回収した。孔および裂孔がないか目視によって検査した。液だめ側試料を、LC/MSアッセイによって、APIの濃度について分析した。
Human cadaver skin transport studies The permeability of APIs in topical formulations was tested using human cadaver skin samples and Franz diffusion cells. Skin segmented human cadaver skin was obtained from a tissue bank, while the Franz diffusion cell was custom built. A human cadaver skin sample sized to fit between the donor and acceptor compartments was placed on a Franz diffusion cell. The topical formulation was weighed (20 mg) and placed on glassine paper with the formulation side facing the skin and firmly fixed. The dosing chamber was covered with paraffin. The reservoir side was filled with physiological saline containing 4% albumin. The reservoir was stirred and maintained at 37° C. by using a drive lock type heater (Aungst B., Fatty Acid Skin Penetration Enhancers. Pharm. Res. 1989; 6(3):244-247). After 4 hours, a 1 mL sample was removed and replaced with 1 mL of saline + 4% albumin. After 24 hours, the entire sump was collected. It was visually inspected for holes and tears. Reservoir side samples were analyzed for API concentration by LC/MS assay.
マウス皮膚輸送試験
局所製剤中のAPIの透過性を、Franz拡散セル内に据付けられた新しく切除したマウス皮膚試料を用いて試験した。実験の4日前に、Balb/cマウスを、ワックス技術を用いて除毛した。実験当日の朝に、マウスを安楽死させて、できるだけ多くの徐毛した皮膚を切除し、洗浄し、使用まで37℃生理食塩水で湿潤状態に維持した。ドナーコンパートメントと受容コンパートメントとの間に適合するようにサイズ合わせされたマウス皮膚試料を、Franz拡散セルのドナーコンパートメントと受容コンパートメントとの間に配置させた。Franzセルの開口部は1cm2であった。局所製剤を秤量し(20mg)、グラシン紙上に置き、製剤側を皮膚に向けて配置させて、しっかりと固定した。投与チャンバーをパラフィンで覆った。4%アルブミンを含有する生理食塩水で液だめ側を充填した。液だめを攪拌し、ドライブロック型ヒーターを使用して、37℃に維持した(Aungst 1989年(上記文献))。4時間後に、1mLの試料を取り出し、生理食塩水+4%アルブミンの1mLで置き換えた。24時間後に、液だめ全体を回収した。孔および裂孔がないか目視によって検査した。液だめ側試料を、LC/MSアッセイによって、APIの濃度について分析した。
Mouse Skin Transport Studies Permeability of APIs in topical formulations was tested using freshly excised mouse skin samples mounted in Franz diffusion cells. Balb/c mice were shaved 4 days before the experiment using wax technology. On the morning of the day of the experiment, the mice were euthanized and as much shaved skin as possible was excised, washed and kept moist with 37°C saline until use. A mouse skin sample sized to fit between the donor and receiving compartments was placed between the donor and receiving compartments of the Franz diffusion cell. The opening of the Franz cell was 1 cm 2 . The topical formulation was weighed (20 mg) and placed on glassine paper with the formulation side facing the skin and firmly fixed. The dosing chamber was covered with paraffin. The reservoir side was filled with physiological saline containing 4% albumin. The sump was stirred and maintained at 37° C. using a drive lock type heater (Aungst 1989 (supra)). After 4 hours, a 1 mL sample was removed and replaced with 1 mL of saline + 4% albumin. After 24 hours, the entire sump was collected. It was visually inspected for holes and tears. Reservoir side samples were analyzed for API concentration by LC/MS assay.
(R)−3−(4−7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル)−3−シクロペンチルプロパンニトリルのヒト死体皮膚を横断する輸送に及ぼす可溶化または分散されたクリーム製剤の強度の影響をまた検討し、そのデータを、表25に概要を示す。分散クリーム製剤(油中水系)の1%w/wから3%w/wへの強度の増加および可溶化クリーム製剤(水中水系)の1%w/wから2%w/wへの強度の増加は、(R)−3−(4−7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル)−3−シクロペンチルプロパンニトリルの輸送において著しい変化はもたらさず、このことは、(R)−3−(4−7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル)−3−シクロペンチルプロパンニトリルのフラックスは、これら製剤のそれぞれからの放出によって限定されないことを示唆している。 Effect of (R)-3-(4-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile on transport across human cadaver skin The effect of strength of the solubilized or dispersed cream formulation was also examined and the data is summarized in Table 25. Increased strength from 1% w/w to 3% w/w of dispersed cream formulations (water-in-oil) and 1% w/w to 2% w/w of solubilized cream formulations (water-in-water) The increase results in a significant change in the transport of (R)-3-(4-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile. However, this means that the flux of (R)-3-(4-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile is It is suggested that the release from each of these formulations is not limiting.
新しく切除されたマウス皮膚を横断する(R)−3−(4−7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル)−3−シクロペンチルプロパンニトリルの輸送を、齧歯類薬理試験(表26)で用いられた製剤を使用して更に評価した。可溶化クリームの強度が0.5〜1.5%に増加された場合、透過性が増大する一般的傾向があったが、これら傾向は、分散製剤では認められなかった。可溶化クリームについて、24時間にわたってマウス皮膚を横断輸送された(R)−3−(4−7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル)−3−シクロペンチルプロパンニトリルの平均累加量は、ヒト死体皮膚試験でみられたものよりも約20倍高かった(全ての実験の累加平均)。 Of (R)-3-(4-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile across freshly excised mouse skin Transport was further evaluated using the formulation used in the rodent pharmacology study (Table 26). There was a general tendency for increased permeability when the strength of the solubilized cream was increased to 0.5-1.5%, but these tendencies were not observed in the dispersed formulations. For the solubilized cream, (R)-3-(4-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)- transported across mouse skin for 24 hours. The average cumulative dose of 3-cyclopentylpropanenitrile was about 20 times higher than that seen in the human cadaver skin test (cumulative average of all experiments).
(R)−3−(4−7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル)−3−シクロペンチルプロパンニトリルリン酸塩の溶解度に基づいて、1.5%の最大薬剤負荷が、水中油(可溶化クリーム)製剤で可能であった。2種のクリーム製剤の中で、水中油(可溶化クリーム)生成物がより良好な物理的安定性を示した(上記の表21参照)。分散製剤において3%より高い強度および可溶化クリーム製剤において2%より高い強度は、薬剤物質が溶液から結晶化したために、制御された室温での数日間の貯蔵後を超えては、物理的に安定ではなかったことに留意されたい。皮膚透過性試験、製造能力データ、ならびに製剤の初期段階で得られた物理的および化学的特性データとともに、これらの結果に基づいて、水中油エマルジョン系(1.5%w/wの最大強度を有する)を備える可溶化クリームが更なる開発のために選択された。 Based on the solubility of (R)-3-(4-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate, 1 A maximum drug load of 0.5% was possible with the oil-in-water (solubilized cream) formulation. Of the two cream formulations, the oil-in-water (solubilized cream) product showed better physical stability (see Table 21 above). Strengths higher than 3% in the dispersion formulation and strengths higher than 2% in the solubilized cream formulation are physically greater than after several days of storage at controlled room temperature due to the drug substance crystallizing out of solution. Note that it was not stable. Based on these results, along with skin permeability tests, manufacturability data, and physical and chemical property data obtained in the early stages of formulation, an oil-in-water emulsion system (maximum strength of 1.5% w/w Solubilized cream with) was selected for further development.
実施例7:製剤での乾癬の臨床治療
慢性尋常性乾癬の約200人の被験者が、二重盲検、プラセボ対照試験に登録された。4つの用量群があり、これらは3つの実薬投与群およびビヒクル群であった。実薬投与群は、0.5%、1.0%、および1.5%w/w水中油製剤(前記実施例3を参照)で処置された。約50人の被験者を、それぞれの処置群に無作為割付した。クリームの薄層を一日一回、尋常性乾癬の20%の体表面積まで塗布した。処置は84日間適用され、効果を病斑スコアの変化によって測定した(図2)。病斑スコアは、紅斑の量、斑の落屑および厚さを評価する測定尺度である。APIの1%w/wまたは1.5%w/wに無作為割付された患者の25%が、12週で消失されたまたはほとんど消失された病巣を有したのに対して、ビヒクル群では6%であった。
Example 7: Clinical Treatment of Psoriasis With a Formulation Approximately 200 subjects with chronic plaque psoriasis were enrolled in a double-blind, placebo-controlled trial. There were 4 dose groups, these were the 3 active treatment groups and the vehicle group. Active dose groups were treated with 0.5%, 1.0%, and 1.5% w/w oil-in-water formulations (see Example 3 above). About 50 subjects were randomly assigned to each treatment group. A thin layer of cream was applied once daily to a body surface area of 20% of psoriasis vulgaris. The treatment was applied for 84 days and the effect was measured by the change in lesion score (Fig. 2). The lesion score is a metric that evaluates the amount of erythema, desquamation and thickness of the spot. Twenty-five percent of patients randomly assigned to 1% w/w or 1.5% w/w of the API had lesions that disappeared or disappeared at 12 weeks, whereas in the vehicle group It was 6%.
病巣部位のサブセットで、写真についてインフォームドコンセントに署名した被験者から写真が取得された。画像はベースライン(試験治療の最初の適用前)および84日目(試験治療の最終適用日)で得られた(図3〜7を参照)。これら写真は、水中油製剤で処置された被験者のサブセットの代表的なものである。 Pictures were obtained from subjects who signed informed consent for the pictures in a subset of lesion sites. Images were acquired at baseline (prior to the first application of study treatment) and on Day 84 (date of last application of study treatment) (see Figures 3-7). These pictures are representative of a subset of subjects treated with the oil-in-water formulation.
実施例8:ネズミ皮膚接触遅延型過敏応答試験
本明細書で記載される製剤はまた、T細胞誘導ネズミ遅延型過敏応答試験モデルにおいてもそれらの有効性について試験することができる。ネズミ皮膚接触遅延型過敏(DTH)応答は、臨床的接触性皮膚炎、および乾癬のような皮膚の他のTリンパ球介在免疫疾患の有効な動物モデルであるとされている(Immunol Today.1998 Jan;19(1):37〜44頁)。ネズミDTHは、免疫性浸潤物、付随的な炎症性サイトカインでの増加、および角質細胞過剰増殖を含む乾癬での複数の特徴を共有する。更には、医療機関における乾癬の治療で有効性を有する多くの部類の薬剤がまた、マウスでのDTH応答の効果的な阻害剤である(Agents Action.1993 Jan;38(1−2)116〜21頁)。
Example 8: Murine Skin Contact Delayed Hypersensitivity Response Test The formulations described herein can also be tested for their efficacy in a T cell-induced murine delayed hypersensitivity test model. The murine skin contact delayed type hypersensitivity (DTH) response has been described as an effective animal model for clinical contact dermatitis and other T lymphocyte mediated immune disorders of the skin such as psoriasis (Immunol Today. 1998). Jan; 19(1):37-44). Murine DTH shares multiple features in psoriasis including immune infiltrates, an increase in concomitant inflammatory cytokines, and keratinocyte hyperproliferation. Furthermore, many classes of drugs that have efficacy in the treatment of psoriasis in medical institutions are also effective inhibitors of the DTH response in mice (Agents Action. 1993 Jan; 38(1-2)116-. 21).
0日目および1日目に、Balb/cマウスに、その剃った腹部に抗原2,4,ジニトロ−フルオロベンゼン(DNFB)を使用して、局所塗布によって感作を起こさせる。5日目に、エンジニアのマイクロメーターを使用してマウスの耳の厚さを測定する。この測定値を記録し、ベースラインとして用いる。次いで動物の両耳に、濃度0.2%で、合計で20μL(内耳介上に10μLおよび外耳介上に10μL)のDNFBの局所塗布によって抗原投与する。抗原投与から24時間〜72時間後に、耳の厚さを再び測定する。試験製剤による処置を、感作および抗原投与段階の全体にわたって行う(1日目〜7日目)か、若しく抗原投与の前および抗原投与段階の全体を通して(通常、4日目の午後〜7日目)に行う。試験化合物(異なる濃度での)の処置は、局所的に投与される(耳への治療剤の局所塗布)。試験製剤の有効性は、処置されていない状態と比較しての耳の浮腫での減少によって示される。20%またはそれ以上の減少を起こす化合物が有効であるとみなされる。いくつかの実験では、マウスに抗原投与されるが、感作されないものがある(陰性対照)。 On days 0 and 1, Balb/c mice are sensitized by topical application with the antigen 2,4,dinitro-fluorobenzene (DNFB) on their shaved abdomen. On day 5, mouse ear thickness is measured using an engineer's micrometer. Record this measurement and use it as a baseline. The animals are then challenged with a total concentration of 0.2 μL (10 μL on the inner ear and 10 μL on the outer ear) at a concentration of 0.2% by topical application of DNFB. Ear thickness is measured again 24 to 72 hours after challenge. Treatment with the test formulation is performed throughout the sensitization and challenge phase (Days 1-7), or prior to challenge and throughout the challenge phase (usually afternoon 4-7 PM). Day 1). Treatment with test compound (at different concentrations) is administered topically (topical application of therapeutic agent to the ear). Efficacy of the test formulation is shown by a reduction in ear edema compared to the untreated condition. Compounds that cause a 20% or greater reduction are considered effective. In some experiments, mice were challenged but not sensitized (negative control).
試験製剤の阻害効果(JAK−STAT経路の阻害活性)は、免疫組織学的分析によって確認され得る。JAK−STAT経路(複数可)の活性化は、機能的転写因子の形成および転座をもたらす。更に、免疫細胞の流入および増大した角質細胞の増殖はまた、評価かつ定量され得る耳での特徴的な発現プロファイルの変化ももたらすはずである。ホルマリン固定され、パラフィン埋包された耳断片(DTHモデルで抗原投与段階後に採取)を、リン酸化STAT3と特異的に相互作用する抗体(クローン58E12、Cell Signaling Technologies)を用いて、免疫組織学的分析に供する。比較のために、DTHモデルにおいて、マウスの耳は、試験製剤、ビヒクル、またはデキサメタゾン(乾癬のために臨床的に有効な治療)で処置されるか、もしくはいかなる処置も行わない。試験製剤およびデキサメタゾンは、定性的および定量的の双方で同様な転写性変化を生み出し得、試験製剤およびデキサメタゾンの両者が浸潤細胞の数を減らし得る。試験化合物の局所投与は、阻害効果、すなわち、浸潤細胞の数の減少および転写変化の阻害を引き起こし得る。 The inhibitory effect of the test preparation (inhibitory activity of JAK-STAT pathway) can be confirmed by immunohistological analysis. Activation of the JAK-STAT pathway(s) results in the formation and translocation of functional transcription factors. Furthermore, the influx of immune cells and increased keratinocyte proliferation should also lead to changes in the characteristic expression profile in the ear that can be evaluated and quantified. Formalin-fixed and paraffin-embedded ear fragments (collected after the challenge step in DTH model) were immunohistologically examined using an antibody (clone 58E12, Cell Signaling Technologies) that specifically interacts with phosphorylated STAT3. Provide for analysis. For comparison, in the DTH model, mouse ears are treated with the test formulation, vehicle, or dexamethasone (a clinically effective treatment for psoriasis) or no treatment. The test formulation and dexamethasone can produce similar transcriptional changes both qualitatively and quantitatively, and both the test formulation and dexamethasone can reduce the number of infiltrating cells. Topical administration of the test compound may cause an inhibitory effect, ie a reduction in the number of infiltrating cells and an inhibition of transcriptional changes.
本発明は、以下のものを包含する。
[発明1]
局所的皮膚適用のための医薬製剤であり、
水中油エマルジョン、および
(R)−3−シクロペンチル−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]プロパンニトリルまたはその医薬上許容される塩である治療剤の治療的に有効な量
を含む医薬製剤。
[発明2]
エマルジョンが、水、油成分および乳化剤成分を含む、上記の発明1に記載の医薬製剤。
[発明3]
油成分が、製剤の約10重量%〜約40重量%の量で存在する、上記の発明2に記載の医薬製剤。
[発明4]
油成分が、製剤の約17重量%〜約27重量%の量で存在する、上記の発明2に記載の医薬製剤。
[発明5]
油成分が、製剤の約20重量%〜約27重量%の量で存在する、上記の発明2に記載の医薬製剤。
[発明6]
油成分が、ワセリン、脂肪アルコール、鉱油、トリグリセリドおよびシリコーン油から独立して選択される1つ以上の物質を含む、上記の発明2〜5のいずれか1つに記載の医薬製剤。
[発明7]
油成分が、白色ワセリン、セチルアルコール、ステアリルアルコール、軽質鉱油、中鎖トリグリセリドおよびジメチコーンから独立して選択される1つ以上の物質を含む、上記の発明2〜5のいずれか1つに記載の医薬製剤。
[発明8]
油成分が密封剤成分を含む、上記の発明2に記載の医薬製剤。
[発明9]
密封剤成分が、製剤の約2重量%〜約15重量%の量で存在する、上記の発明8に記載の医薬製剤。
[発明10]
密封剤成分が、前記製剤の約5重量%〜約10重量%の量で存在する、上記の発明8に記載の医薬製剤。
[発明11]
密封剤成分がワセリンを含む、上記の発明8〜10のいずれか1つに記載の医薬製剤。
[発明12]
密封剤成分が白色ワセリンを含む、上記の発明8〜10のいずれか1つに記載の医薬製剤。
[発明13]
油成分が、硬化剤成分を含む、上記の発明2に記載の医薬製剤。
[発明14]
硬化剤成分が、製剤の約2重量%〜約8重量%の量で存在する、上記の発明13に記載の医薬製剤。
[発明15]
硬化剤成分が、製剤の約3重量%〜約6重量%の量で存在する、上記の発明13に記載の医薬製剤。
[発明16]
硬化剤成分が、製剤の約4重量%〜約7重量%の量で存在する、上記の発明13に記載の医薬製剤。
[発明17]
硬化剤成分が、脂肪アルコールから独立して選択される1つ以上の物質を含む、上記の発明13〜16のいずれか1つに記載の医薬製剤。
[発明18]
硬化剤成分が、C12−20脂肪アルコールから独立して選択される1つ以上の物質を含む、上記の発明13〜16のいずれか1つに記載の医薬製剤。
[発明19]
硬化剤成分が、C16−18脂肪アルコールから独立して選択される1つ以上の物質を含む、上記の発明13〜16のいずれか1つに記載の医薬製剤。
[発明20]
硬化剤成分が、セチルアルコールおよびステアリルアルコールから独立して選択される1つ以上の物質を含む、上記の発明13〜16のいずれか1つに記載の医薬製剤。
[発明21]
油成分が、皮膚軟化剤成分含む、上記の発明2に記載の医薬製剤。
[発明22]
皮膚軟化剤成分が、製剤の約5重量%〜約15重量%の量で存在する、上記の発明21に記載の医薬製剤。
[発明23]
皮膚軟化剤成分が、製剤の約7重量%〜約13重量%の量で存在する、上記の発明21に記載の医薬製剤。
[発明24]
皮膚軟化剤成分が、鉱油およびトリグリセリドから独立して選択される1つ以上の物質を含む、上記の発明21〜23のいずれか1つに記載の医薬製剤。
[発明25]
皮膚軟化剤成分が、軽質鉱油および中鎖トリグリセリドから独立して選択される1つ以上の物質を含む、上記の発明21〜23のいずれか1つに記載の医薬製剤。
[発明26]
皮膚軟化剤成分が、軽質鉱油、中鎖トリグリセリドおよびジメチコーンから独立して選択される1つ以上の物質を含む、上記の発明21〜23のいずれか1つに記載の医薬製剤。
[発明27]
水が、製剤の約35重量%〜約65重量%の量で存在する、上記の発明2〜26のいずれか1つに記載の医薬製剤。
[発明28]
水が、製剤の約40重量%〜約60重量%の量で存在する、上記の発明2〜26のいずれか1つに記載の医薬製剤。
[発明29]
水が、製剤の約45重量%〜約55重量%の量で存在する、上記の発明2〜26のいずれか1つに記載の医薬製剤。
[発明30]
乳化剤成分が、製剤の約1重量%〜約9重量%の量で存在する、上記の発明2〜29のいずれか1つに記載の医薬製剤。
[発明31]
乳化剤成分が、前記製剤の約2重量%〜約6重量%の量で存在する、上記の発明2〜29のいずれか1つに記載の医薬製剤。
[発明32]
乳化剤成分が、前記製剤の約3重量%〜約5重量%の量で存在する、上記の発明2〜29のいずれか1つに記載の医薬製剤。
[発明33]
乳化剤成分が、前記製剤の約4重量%〜約7重量%の量で存在する、上記の発明2〜29のいずれか1つに記載の医薬製剤。
[発明34]
医薬製剤が、乳化剤成分および硬化剤成分を含み、乳化剤成分と硬化剤成分との合計量が、製剤の少なくとも約8重量%である、上記の発明2〜29のいずれか1つに記載の医薬製剤。
[発明35]
乳化剤成分が、グリセリル脂肪エステルおよびソルビタン脂肪エステルから独立して選択される1つ以上の物質を含む、上記の発明2〜34のいずれか1つに記載の医薬製剤。
[発明36]
乳化剤成分が、グリセリルステアレートおよびポリソルベート20から独立して選択される1つ以上の物質を含む、上記の発明2〜34のいずれか1つに記載の医薬製剤。
[発明37]
医薬製剤が、さらに安定化剤成分を含む、上記の発明1〜36のいずれか1つに記載の医薬製剤。
[発明38]
安定化剤成分が、製剤の約0.05重量%〜約5重量%の量で存在する、上記の発明37に記載の医薬製剤。
[発明39]
安定化剤成分が、製剤の約0.1重量%〜約2重量%の量で存在する、上記の発明37に記載の医薬製剤。
[発明40]
安定化剤成分が、製剤の約0.3重量%〜約0.5重量%の量で存在する、上記の発明37に記載の医薬製剤。
[発明41]
安定化剤成分が、多糖類から独立して選択される1つ以上の物質を含む、上記の発明37〜40のいずれか1つに記載の医薬製剤。
[発明42]
安定化剤成分が、キサンタンガムを含む、上記の発明37〜40のいずれか1つに記載の医薬製剤。
[発明43]
医薬製剤が、さらに溶媒成分を含む、上記の発明1〜42のいずれか1つに記載の医薬製剤。
[発明44]
溶媒成分が、製剤の約10重量%〜約35重量%の量で存在する、上記の発明43に記載の医薬製剤。
[発明45]
溶媒成分が、製剤の約15重量%〜約30重量%の量で存在する、上記の発明43に記載の医薬製剤。
[発明46]
溶媒成分が、製剤の約20重量%〜約25重量%の量で存在する、上記の発明43に記載の医薬製剤。
[発明47]
溶媒成分が、アルキレングリコールおよびポリアルキレングリコールから独立して選択される1つ以上の物質を含む、上記の発明43〜46のいずれか1つに記載の医薬製剤。
[発明48]
溶媒成分が、プロピレングリコールおよびポリエチレングリコールから独立して選択される1つ以上の物質を含む、上記の発明43〜46のいずれか1つに記載の医薬製剤。
[発明49]
治療剤が、遊離塩基を基準にして、製剤の約0.5重量%〜約1.5重量%の量で存在する、上記の発明1〜48のいずれか1つに記載の医薬製剤。
[発明50]
治療剤が、遊離塩基を基準にして、製剤の約0.5重量%の量で存在する、上記の発明1〜48のいずれか1つに記載の医薬製剤。
[発明51]
治療剤が、遊離塩基を基準にして、製剤の約1重量%の量で存在する、上記の発明1〜48のいずれか1つに記載の医薬製剤。
[発明52]
治療剤が、遊離塩基を基準にして、製剤の約1.5重量%の量で存在する、上記の発明1〜48のいずれか1つに記載の医薬製剤。
[発明53]
治療剤が、(R)−3−シクロペンチル−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]プロパンニトリルリン酸塩である、上記の発明1〜52のいずれか1つに記載の医薬製剤。
[発明54]
製剤の約35重量%〜約65重量%の水、
製剤の約10重量%〜約40重量%の油成分、
製剤の約1重量%〜約9重量%の乳化剤成分、
製剤の約10重量%〜約35重量%の溶媒成分、
製剤の約0.05重量%〜約5重量%の安定化剤成分、および
遊離塩基を基準にして、製剤の約0.5重量%〜約1.5重量%の(R)−3−シクロペンチル−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]プロパンニトリルまたはその医薬上許容される塩
を含む、上記の発明1に記載の医薬製剤。
[発明55]
製剤の約40重量%〜約60重量%の水、
製剤の約15重量%〜約30重量%の油成分、
製剤の約2重量%〜約6重量%の乳化剤成分、
製剤の約15重量%〜約30重量%の溶媒成分、
製剤の約0.1重量%〜約2重量%の安定化剤成分、および
遊離塩基を基準にして、製剤の約0.5重量%〜約1.5重量%の(R)−3−シクロペンチル−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]プロパンニトリルまたはその医薬上許容される塩
を含む、上記の発明1に記載の医薬製剤。
[発明56]
製剤の約45重量%〜約55重量%の水、
製剤の約17重量%〜約27重量%の油成分、
製剤の約3重量%〜約5重量%の乳化剤成分、
製剤の約20重量%〜約25重量%の溶媒成分、
製剤の約0.3重量%〜約0.5重量%の安定化剤成分、および
遊離塩基を基準にして、製剤の約0.5重量%〜約1.5重量%の(R)−3−シクロペンチル−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]プロパンニトリルまたはその医薬上許容される塩
を含む、上記の発明1に記載の医薬製剤。
[発明57]
製剤の約45重量%〜約55重量%の水、
製剤の約17重量%〜約27重量%の油成分、
製剤の約4重量%〜約7重量%の乳化剤成分、
製剤の約20重量%〜約25重量%の溶媒成分、
製剤の約0.3重量%〜約0.5重量%の安定化剤成分、および
遊離塩基を基準にして、製剤の約0.5重量%〜約1.5重量%の(R)−3−シクロペンチル−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]プロパンニトリルまたはその医薬上許容される塩
を含む、上記の発明1に記載の医薬製剤。
[発明58]
油成分が、ワセリン、脂肪アルコール、鉱油、トリグリセリドおよびジメチコーンから独立して選択される1つ以上の物質を含み、
乳化剤成分が、グリセリル脂肪エステルおよびソルビタン脂肪エステルから独立して選択される1つ以上の物質を含み、
溶媒成分が、アルキレングリコールおよびポリアルキレングリコールから独立して選択される1つ以上の物質を含み、
安定化剤成分が、多糖類から独立して選択される1つ以上の物質を含む、
上記の発明54〜57のいずれか1つに記載の医薬製剤。
[発明59]
油成分が、白色ワセリン、セチルアルコール、ステアリルアルコール、軽質鉱油、中鎖トリグリセリドおよびジメチコーンから独立して選択される1つ以上の物質を含み、
乳化剤成分が、グリセリルステアレートおよびポリソルベート20から独立して選択される1つ以上の物質を含み、
溶媒成分が、プロピレングリコールおよびポリエチレングリコールから独立して選択される1つ以上の物質を含み、
安定化剤成分が、キサンタンガムを含む、
上記の発明54〜57のいずれか1つに記載の医薬製剤。
[発明60]
製剤の約35重量%〜約60重量%の水、
製剤の約2重量%〜約15重量%の密封剤成分、
製剤の約2重量%〜約8重量%の硬化剤成分、
製剤の約5重量%〜約15重量%の皮膚軟化剤成分、
製剤の約1重量%〜約9重量%の乳化剤成分、
製剤の約0.05重量%〜約5重量%の安定化剤成分、
製剤の約10重量%〜約35重量%の溶媒成分、および
遊離塩基を基準にして、製剤の約0.5重量%〜約1.5重量%の(R)−3−シクロペンチル−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]プロパンニトリルまたはその医薬上許容される塩
を含む、上記の発明1に記載の医薬製剤。
[発明61]
製剤の約40重量%〜約60重量%の水、
製剤の約5重量%〜約10重量%の密封剤成分、
製剤の約2重量%〜約8重量%の硬化剤成分、
製剤の約7重量%〜約12重量%の皮膚軟化剤成分、
製剤の約2重量%〜約6重量%の乳化剤成分、
製剤の約0.1重量%〜約2重量%の安定化剤成分、
製剤の約15重量%〜約30重量%の溶媒成分、および
遊離塩基を基準にして、製剤の約0.5重量%〜約1.5重量%の(R)−3−シクロペンチル−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]プロパンニトリルまたはその医薬上許容される塩
を含む、上記の発明1に記載の医薬製剤。
[発明62]
製剤の約45重量%〜約55重量%の水、
製剤の約5重量%〜約10重量%の密封剤成分、
製剤の約3重量%〜約6重量%の硬化剤成分、
製剤の約7重量%〜約13重量%の皮膚軟化剤成分、
製剤の約3重量%〜約5重量%の乳化剤成分、
製剤の約0.3重量%〜約0.5重量%の安定化剤成分、
製剤の約20重量%〜約25重量%の溶媒成分、および
遊離塩基を基準にして、製剤の約0.5重量%〜約1.5重量%の(R)−3−シクロペンチル−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]プロパンニトリルまたはその医薬上許容される塩
を含む、上記の発明1に記載の医薬製剤。
[発明63]
製剤の約45重量%〜約55重量%の水、
製剤の約5重量%〜約10重量%の密封剤成分、
製剤の約4重量%〜約7重量%の硬化剤成分、
製剤の約7重量%〜約13重量%の皮膚軟化剤成分、
製剤の約4重量%〜約7重量%の乳化剤成分、
製剤の約0.3重量%〜約0.5重量%の安定化剤成分、
製剤の約20重量%〜約25重量%の溶媒成分、および
遊離塩基を基準にして、製剤の約0.5重量%〜約1.5重量%の(R)−3−シクロペンチル−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]プロパンニトリルまたはその医薬上許容される塩
を含む、上記の発明1に記載の医薬製剤。
[発明64]
製剤の約45重量%〜約55重量%の水、
製剤の約7重量%の密封剤成分、
製剤の約4.5重量%〜約5重量%の硬化剤成分、
製剤の約10重量%の皮膚軟化剤成分、
製剤の約4重量%〜約4.5重量%の乳化剤成分、
製剤の約0.4重量%の安定化剤成分、
製剤の約22重量%の溶媒成分、および
遊離塩基を基準にして、製剤の約0.5重量%〜約1.5重量%の(R)−3−シクロペンチル−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]プロパンニトリルまたはその医薬上許容される塩
を含む、上記の発明1に記載の医薬製剤。
[発明65]
硬化剤成分と乳化剤成分の合計量が、製剤の少なくとも約8重量%である、上記の発明60〜64のいずれか1つに記載の医薬製剤。
[発明66]
密封剤成分が、ワセリンを含み、
硬化剤成分が、1つ以上の脂肪アルコールから独立して選択される1つ以上の物質を含み、
皮膚軟化剤成分が、鉱油およびトリグリセリドから独立して選択される1つ以上の物質を含み、
乳化剤成分が、グリセリル脂肪エステルおよびソルビタン脂肪エステルから独立して選択される1つ以上の物質を含み、
安定化剤成分が、多糖類から独立して選択される1つ以上の物質を含み、
溶媒成分が、アルキレングリコールおよびポリアルキレングリコールから独立して選択される1つ以上の物質を含む、
上記の発明60〜65のいずれか1つに記載の医薬製剤。
[発明67]
密封剤成分が、白色ワセリンを含み、
硬化剤成分が、セチルアルコールおよびステアリルアルコールから独立して選択される1つ以上の物質を含み、
皮膚軟化剤成分が、軽質鉱油、中鎖トリグリセリドおよびジメチコーンから独立して選択される1つ以上の物質を含み、
乳化剤成分が、グリセリルステアレートおよびポリソルベート20から独立して選択される1つ以上の物質を含み、
安定化剤成分が、キサンタンガムを含み、
溶媒成分が、プロピレングリコールおよびポリエチレングリコールから独立して選択される1つ以上の物質を含む、
上記の発明60〜65のいずれか1つに記載の医薬製剤。
[発明68]
さらに抗菌性保存剤成分を含む、上記の発明1〜67のいずれか1つに記載の医薬製剤。
[発明69]
抗菌性保存剤成分が、製剤の約0.05重量%〜約3重量%の存在する、上記の発明68に記載の医薬製剤。
[発明70]
抗菌性保存剤成分が、製剤の約0.1重量%〜約1重量%の存在する、上記の発明68に記載の医薬製剤。
[発明71]
抗菌性保存剤成分が、アルキルパラベンおよびフェノキシエタノールから独立して選択される1つ以上の物質を含む、上記の発明68〜70のいずれか1つに記載の医薬製剤。
[発明72]
抗菌性保存剤成分が、メチルパラベン、プロピルパラベンおよびフェノキシエタノールから独立して選択される1つ以上の物質を含む、上記の発明68〜70のいずれか1つに記載の医薬製剤。
[発明73]
さらにキレート剤成分を含む、上記の発明1〜72のいずれか1つに記載の医薬製剤。
[発明74]
キレート剤成分が、エデト酸二ナトリウムを含む、上記の発明73に記載の医薬製剤。
[発明75]
皮膚障害の治療を必要とする患者における皮膚障害の治療方法であり、該患者の皮膚の領域に上記の発明1〜74のいずれか1つに記載の医薬製剤を投与することを含む、方法。
[発明76]
皮膚障害が、アトピー性皮膚炎または乾癬である、上記の発明75に記載の方法。
[発明77]
皮膚障害が乾癬である、上記の発明75に記載の方法。
[発明78]
皮膚障害が、皮膚感作、皮膚刺激、皮疹、接触性皮膚炎またはアレルギー性接触感作である、上記の発明75に記載の方法。
[発明79]
皮膚障害が、水疱性皮膚障害である、上記の発明75に記載の方法。
[発明80]
水疱性皮膚障害が、尋常性天疱瘡(PV)または水疱性類天疱瘡(BP)である、上記の発明79に記載の方法。
[発明81]
皮膚障害の治療を必要とする患者の皮膚障害治療用の上記の発明1〜74のいずれか1つに記載の医薬製剤。
[発明82]
皮膚障害の治療を必要とする患者の皮膚障害治療用の薬剤の調製のための上記の発明1〜74のいずれか1つに記載の医薬製剤の使用。
本明細書に記載されるものに加えて、本発明の種々の変形が、前述の説明から当業者には明らかであろう。このような変形も特許請求の範囲内に包含されることが意図されている。本出願で引用される各参考文献は、その全体が参照により本明細書に組み込まれる。
The present invention includes the following.
[Invention 1]
A pharmaceutical formulation for topical dermal application,
Oil-in-water emulsion, and (R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile or its pharmaceutically A pharmaceutical formulation comprising a therapeutically effective amount of a therapeutic agent that is an acceptable salt.
[Invention 2]
The pharmaceutical formulation according to invention 1 above, wherein the emulsion comprises water, an oil component and an emulsifier component.
[Invention 3]
The pharmaceutical formulation according to invention 2 above, wherein the oil component is present in an amount of about 10% to about 40% by weight of the formulation.
[Invention 4]
The pharmaceutical formulation according to invention 2 above, wherein the oil component is present in an amount of about 17% to about 27% by weight of the formulation.
[Invention 5]
The pharmaceutical formulation according to invention 2 above, wherein the oil component is present in an amount of about 20% to about 27% by weight of the formulation.
[Invention 6]
The pharmaceutical formulation according to any one of the above inventions 2-5, wherein the oil component comprises one or more substances independently selected from petrolatum, fatty alcohols, mineral oils, triglycerides and silicone oils.
[Invention 7]
The oil component comprises one or more substances independently selected from white petrolatum, cetyl alcohol, stearyl alcohol, light mineral oil, medium chain triglycerides and dimethicone. Pharmaceutical formulation.
[Invention 8]
The pharmaceutical formulation according to invention 2 above, wherein the oil component comprises a sealant component.
[Invention 9]
The pharmaceutical formulation according to invention 8 above, wherein the sealant component is present in an amount of about 2% to about 15% by weight of the formulation.
[Invention 10]
The pharmaceutical formulation according to invention 8 above, wherein the sealant component is present in an amount of about 5% to about 10% by weight of the formulation.
[Invention 11]
The pharmaceutical preparation according to any one of the above inventions 8 to 10, wherein the sealant component contains petrolatum.
[Invention 12]
The pharmaceutical preparation according to any one of the above inventions 8 to 10, wherein the sealant component comprises white petrolatum.
[Invention 13]
The pharmaceutical preparation according to the above-mentioned invention 2, wherein the oil component contains a curing agent component.
[Invention 14]
The pharmaceutical formulation according to invention 13 above, wherein the hardener component is present in an amount of about 2% to about 8% by weight of the formulation.
[Invention 15]
The pharmaceutical formulation according to invention 13 above, wherein the hardener component is present in an amount of about 3% to about 6% by weight of the formulation.
[Invention 16]
The pharmaceutical formulation according to invention 13 above, wherein the hardener component is present in an amount of about 4% to about 7% by weight of the formulation.
[Invention 17]
17. A pharmaceutical formulation according to any one of inventions 13 to 16 above, wherein the hardener component comprises one or more substances independently selected from fatty alcohols.
[Invention 18]
17. A pharmaceutical formulation according to any one of inventions 13 to 16 above, wherein the hardener component comprises one or more substances independently selected from C12-20 fatty alcohols.
[Invention 19]
17. A pharmaceutical formulation according to any one of inventions 13 to 16 above, wherein the hardener component comprises one or more substances independently selected from C16-18 fatty alcohols.
[Invention 20]
17. A pharmaceutical formulation according to any one of inventions 13 to 16 above, wherein the hardener component comprises one or more substances independently selected from cetyl alcohol and stearyl alcohol.
[Invention 21]
The pharmaceutical preparation according to the above-mentioned invention 2, wherein the oil component contains an emollient component.
[Invention 22]
The pharmaceutical formulation according to invention 21 above, wherein the emollient component is present in an amount of about 5% to about 15% by weight of the formulation.
[Invention 23]
The pharmaceutical formulation according to invention 21 above, wherein the emollient component is present in an amount of about 7% to about 13% by weight of the formulation.
[Invention 24]
The pharmaceutical formulation according to any one of inventions 21 to 23 above, wherein the emollient component comprises one or more substances independently selected from mineral oil and triglycerides.
[Invention 25]
The pharmaceutical formulation according to any one of the above inventions 21-23, wherein the emollient component comprises one or more substances independently selected from light mineral oil and medium chain triglycerides.
[Invention 26]
The pharmaceutical formulation according to any one of the above inventions 21-23, wherein the emollient component comprises one or more substances independently selected from light mineral oil, medium chain triglycerides and dimethicone.
[Invention 27]
The pharmaceutical formulation according to any one of inventions 2 to 26 above, wherein water is present in an amount of about 35% to about 65% by weight of the formulation.
[Invention 28]
The pharmaceutical formulation according to any one of inventions 2 to 26 above, wherein water is present in an amount of about 40% to about 60% by weight of the formulation.
[Invention 29]
The pharmaceutical formulation according to any one of inventions 2 to 26 above, wherein water is present in an amount of about 45% to about 55% by weight of the formulation.
[Invention 30]
30. The pharmaceutical formulation according to any one of inventions 2-29 above, wherein the emulsifier component is present in an amount of about 1% to about 9% by weight of the formulation.
[Invention 31]
30. A pharmaceutical formulation according to any one of inventions 2 to 29 above wherein the emulsifier component is present in an amount of about 2% to about 6% by weight of the formulation.
[Invention 32]
30. The pharmaceutical formulation according to any one of inventions 2-29 above, wherein the emulsifier component is present in an amount of about 3% to about 5% by weight of the formulation.
[Invention 33]
30. The pharmaceutical formulation according to any one of inventions 2 to 29 above, wherein the emulsifier component is present in an amount of about 4% to about 7% by weight of the formulation.
[Invention 34]
The pharmaceutical agent according to any one of the above inventions 2 to 29, wherein the pharmaceutical preparation comprises an emulsifier component and a curing agent component, and the total amount of the emulsifier component and the curing agent component is at least about 8% by weight of the formulation. Formulation.
[Invention 35]
The pharmaceutical formulation according to any one of the above inventions 2-34, wherein the emulsifier component comprises one or more substances independently selected from glyceryl fatty esters and sorbitan fatty esters.
[Invention 36]
35. A pharmaceutical formulation according to any one of inventions 2-34 above, wherein the emulsifier component comprises one or more substances independently selected from glyceryl stearate and polysorbate 20.
[Invention 37]
The pharmaceutical preparation according to any one of the above inventions 1 to 36, wherein the pharmaceutical preparation further comprises a stabilizer component.
[Invention 38]
38. The pharmaceutical formulation according to invention 37 above, wherein the stabilizer component is present in an amount of about 0.05% to about 5% by weight of the formulation.
[Invention 39]
38. The pharmaceutical formulation according to invention 37 above, wherein the stabilizer component is present in an amount of about 0.1% to about 2% by weight of the formulation.
[Invention 40]
38. The pharmaceutical formulation according to invention 37 above, wherein the stabilizer component is present in an amount of about 0.3% to about 0.5% by weight of the formulation.
[Invention 41]
41. A pharmaceutical formulation according to any one of the above inventions 37-40, wherein the stabilizer component comprises one or more substances independently selected from polysaccharides.
[Invention 42]
41. The pharmaceutical preparation according to any one of the above inventions 37-40, wherein the stabilizer component comprises xanthan gum.
[Invention 43]
The pharmaceutical preparation according to any one of the above inventions 1 to 42, wherein the pharmaceutical preparation further comprises a solvent component.
[Invention 44]
44. The pharmaceutical formulation according to invention 43 above, wherein the solvent component is present in an amount of about 10% to about 35% by weight of the formulation.
[Invention 45]
44. The pharmaceutical formulation according to invention 43 above, wherein the solvent component is present in an amount of about 15% to about 30% by weight of the formulation.
[Invention 46]
44. The pharmaceutical formulation according to invention 43 above, wherein the solvent component is present in an amount of about 20% to about 25% by weight of the formulation.
[Invention 47]
47. A pharmaceutical formulation according to any one of inventions 43 to 46 above, wherein the solvent component comprises one or more substances independently selected from alkylene glycols and polyalkylene glycols.
[Invention 48]
47. A pharmaceutical formulation according to any one of inventions 43 to 46 above, wherein the solvent component comprises one or more substances independently selected from propylene glycol and polyethylene glycol.
[Invention 49]
49. A pharmaceutical formulation according to any one of the above inventions 1-48, wherein the therapeutic agent is present in an amount of about 0.5% to about 1.5% by weight of the formulation, based on the free base.
[Invention 50]
49. A pharmaceutical formulation according to any one of inventions 1 to 48 above, wherein the therapeutic agent is present in an amount of about 0.5% by weight of the formulation, based on the free base.
[Invention 51]
49. A pharmaceutical formulation according to any one of inventions 1 to 48 above, wherein the therapeutic agent is present in an amount of about 1% by weight of the formulation, based on the free base.
[Invention 52]
49. A pharmaceutical formulation according to any one of inventions 1 to 48 above, wherein the therapeutic agent is present in an amount of about 1.5% by weight of the formulation, based on the free base.
[Invention 53]
The therapeutic agent is (R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile phosphate. The pharmaceutical preparation according to any one of the above inventions 1 to 52.
[Invention 54]
From about 35% to about 65% water by weight of the formulation,
About 10% to about 40% by weight of the formulation of the oil component,
About 1% to about 9% by weight of the formulation of an emulsifier component,
About 10% to about 35% by weight of the formulation of the solvent component,
From about 0.05% to about 5% by weight of the formulation of the stabilizer component, and from about 0.5% to about 1.5% by weight of the formulation, based on the free base, of (R)-3-cyclopentyl. The above-mentioned invention 1 containing 3--3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile or a pharmaceutically acceptable salt thereof. The described pharmaceutical preparation.
[Invention 55]
From about 40% to about 60% by weight of the formulation of water,
About 15% to about 30% by weight of the formulation of the oil component,
From about 2% to about 6% by weight of the formulation, an emulsifier component,
About 15% to about 30% by weight of the formulation of the solvent component,
From about 0.1% to about 2% by weight of the formulation of the stabilizer component, and from about 0.5% to about 1.5% by weight of the formulation, based on the free base, of (R)-3-cyclopentyl. The above-mentioned invention 1 containing 3--3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile or a pharmaceutically acceptable salt thereof. The described pharmaceutical preparation.
[Invention 56]
About 45% to about 55% water by weight of the formulation,
From about 17% to about 27% by weight of the formulation of the oil component,
From about 3% to about 5% by weight of the formulation, an emulsifier component,
About 20% to about 25% by weight of the formulation of the solvent component,
From about 0.3% to about 0.5% by weight of the formulation of the stabilizer component, and from about 0.5% to about 1.5% by weight of the formulation, based on the free base, of (R)-3. -Cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile or a pharmaceutically acceptable salt thereof. The pharmaceutical preparation according to 1.
[Invention 57]
About 45% to about 55% water by weight of the formulation,
From about 17% to about 27% by weight of the formulation of the oil component,
From about 4% to about 7% by weight of the formulation, an emulsifier component,
About 20% to about 25% by weight of the formulation of the solvent component,
From about 0.3% to about 0.5% by weight of the formulation of the stabilizer component, and from about 0.5% to about 1.5% by weight of the formulation, based on the free base, of (R)-3. -Cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile or a pharmaceutically acceptable salt thereof. The pharmaceutical preparation according to 1.
[Invention 58]
The oil component comprises one or more substances independently selected from petrolatum, fatty alcohols, mineral oil, triglycerides and dimethicone,
The emulsifier component comprises one or more substances independently selected from glyceryl fatty esters and sorbitan fatty esters,
The solvent component comprises one or more substances independently selected from alkylene glycols and polyalkylene glycols,
The stabilizer component comprises one or more substances independently selected from polysaccharides,
The pharmaceutical preparation according to any one of the above inventions 54 to 57.
[Invention 59]
The oil component comprises one or more substances independently selected from white petrolatum, cetyl alcohol, stearyl alcohol, light mineral oil, medium chain triglycerides and dimethicone,
The emulsifier component comprises one or more substances independently selected from glyceryl stearate and polysorbate 20;
The solvent component comprises one or more substances independently selected from propylene glycol and polyethylene glycol,
The stabilizer component includes xanthan gum,
The pharmaceutical preparation according to any one of the above inventions 54 to 57.
[Invention 60]
From about 35% to about 60% water by weight of the formulation,
About 2% to about 15% by weight of the formulation of the sealant component,
From about 2% to about 8% by weight of the formulation of a hardener component,
About 5% to about 15% by weight of the formulation, an emollient component,
About 1% to about 9% by weight of the formulation of an emulsifier component,
From about 0.05% to about 5% by weight of the formulation of a stabilizer component,
About 10% to about 35% by weight of the formulation of the solvent component, and about 0.5% to about 1.5% by weight of the formulation, based on the free base, of (R)-3-cyclopentyl-3-[ The pharmaceutical preparation according to the above-mentioned invention 1, comprising 4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile or a pharmaceutically acceptable salt thereof. ..
[Invention 61]
From about 40% to about 60% by weight of the formulation of water,
About 5% to about 10% by weight of the formulation of the sealant component,
From about 2% to about 8% by weight of the formulation of a hardener component,
About 7% to about 12% by weight of the formulation, an emollient component,
From about 2% to about 6% by weight of the formulation, an emulsifier component,
From about 0.1% to about 2% by weight of the formulation of a stabilizer component,
About 15% to about 30% by weight of the formulation of the solvent component and about 0.5% to about 1.5% by weight of the formulation of (R)-3-cyclopentyl-3-[based on the free base. The pharmaceutical preparation according to the above-mentioned invention 1, comprising 4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile or a pharmaceutically acceptable salt thereof. ..
[Invention 62]
About 45% to about 55% water by weight of the formulation,
About 5% to about 10% by weight of the formulation of the sealant component,
About 3% to about 6% by weight of the formulation of a hardener component,
About 7% to about 13% by weight of the formulation, an emollient component,
From about 3% to about 5% by weight of the formulation, an emulsifier component,
From about 0.3% to about 0.5% by weight of the formulation of a stabilizer component,
About 20% to about 25% by weight of the formulation of the solvent component, and about 0.5% to about 1.5% by weight of the formulation of (R)-3-cyclopentyl-3-[based on the free base. The pharmaceutical preparation according to the above-mentioned invention 1, comprising 4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile or a pharmaceutically acceptable salt thereof. ..
[Invention 63]
About 45% to about 55% water by weight of the formulation,
About 5% to about 10% by weight of the formulation of the sealant component,
About 4% to about 7% by weight of the formulation of a hardener component,
About 7% to about 13% by weight of the formulation, an emollient component,
From about 4% to about 7% by weight of the formulation, an emulsifier component,
From about 0.3% to about 0.5% by weight of the formulation of a stabilizer component,
About 20% to about 25% by weight of the formulation of the solvent component, and about 0.5% to about 1.5% by weight of the formulation of (R)-3-cyclopentyl-3-[based on the free base. The pharmaceutical preparation according to the above-mentioned invention 1, comprising 4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile or a pharmaceutically acceptable salt thereof. ..
[Invention 64]
About 45% to about 55% water by weight of the formulation,
A sealant component of about 7% by weight of the formulation,
About 4.5% to about 5% by weight of the formulation of a hardener component,
An emollient component of about 10% by weight of the formulation,
From about 4% to about 4.5% by weight of the formulation of the emulsifier component,
About 0.4% by weight of the formulation of a stabilizer component,
About 22% by weight of the formulation of the solvent component, and about 0.5% to about 1.5% by weight of the formulation of (R)-3-cyclopentyl-3-[4-(7H- The pharmaceutical preparation according to Invention 1 above, which comprises pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile or a pharmaceutically acceptable salt thereof.
[Invention 65]
65. The pharmaceutical formulation according to any one of inventions 60 to 64 above, wherein the total amount of hardener component and emulsifier component is at least about 8% by weight of the formulation.
[Invention 66]
The sealant component includes petrolatum,
The hardener component comprises one or more substances independently selected from one or more fatty alcohols,
The emollient component comprises one or more substances independently selected from mineral oils and triglycerides,
The emulsifier component comprises one or more substances independently selected from glyceryl fatty esters and sorbitan fatty esters,
The stabilizer component comprises one or more substances independently selected from polysaccharides,
The solvent component comprises one or more substances independently selected from alkylene glycols and polyalkylene glycols,
The pharmaceutical preparation according to any one of the above inventions 60 to 65.
[Invention 67]
The sealant component includes white petrolatum,
The hardener component comprises one or more substances independently selected from cetyl alcohol and stearyl alcohol,
The emollient component comprises one or more substances independently selected from light mineral oil, medium chain triglycerides and dimethicone,
The emulsifier component comprises one or more substances independently selected from glyceryl stearate and polysorbate 20;
The stabilizer component includes xanthan gum,
The solvent component comprises one or more substances independently selected from propylene glycol and polyethylene glycol,
The pharmaceutical preparation according to any one of the above inventions 60 to 65.
[Invention 68]
The pharmaceutical preparation according to any one of the above inventions 1 to 67, which further comprises an antibacterial preservative component.
[Invention 69]
69. The pharmaceutical formulation according to invention 68 above, wherein the antimicrobial preservative component is present from about 0.05% to about 3% by weight of the formulation.
[Invention 70]
69. A pharmaceutical formulation according to invention 68 above, wherein the antimicrobial preservative component is present from about 0.1% to about 1% by weight of the formulation.
[Invention 71]
71. A pharmaceutical formulation according to any one of inventions 68 to 70 above, wherein the antimicrobial preservative component comprises one or more substances independently selected from alkylparabens and phenoxyethanol.
[Invention 72]
70. A pharmaceutical formulation according to any one of inventions 68 to 70 above, wherein the antimicrobial preservative component comprises one or more substances independently selected from methylparaben, propylparaben and phenoxyethanol.
[Invention 73]
The pharmaceutical preparation according to any one of the above inventions 1 to 72, which further comprises a chelating agent component.
[Invention 74]
74. A pharmaceutical formulation according to invention 73 above, wherein the chelating agent component comprises disodium edetate.
[Invention 75]
A method for treating a skin disorder in a patient in need thereof for treating the skin disorder, the method comprising administering to the skin area of the patient a pharmaceutical formulation according to any one of the above inventions 1-74.
[Invention 76]
The method according to invention 75 above, wherein the skin disorder is atopic dermatitis or psoriasis.
[Invention 77]
The method according to invention 75 above, wherein the skin disorder is psoriasis.
[Invention 78]
The method according to invention 75 above, wherein the skin disorder is skin sensitization, skin irritation, skin rash, contact dermatitis or allergic contact sensitization.
[Invention 79]
The method according to invention 75 above, wherein the skin disorder is bullous skin disorder.
[Invention 80]
82. The method according to invention 79 above, wherein the bullous skin disorder is pemphigus vulgaris (PV) or bullous pemphigoid (BP).
[Invention 81]
The pharmaceutical preparation according to any one of the above inventions 1-74, for the treatment of skin disorders in patients in need of treatment.
[Invention 82]
Use of a pharmaceutical formulation according to any one of the above inventions 1-74 for the preparation of a medicament for the treatment of skin disorders in patients in need of treatment.
Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims. Each reference cited in this application is incorporated herein by reference in its entirety.
Claims (66)
(R)−3−シクロペンチル−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]プロパンニトリルまたはその医薬上許容される塩である治療剤
を含む、皮膚障害治療用の局所的皮膚適用のための医薬製剤であって、
前記水中油エマルジョンがクリームを形成し、
前記治療剤が遊離塩基を基準にして前記製剤の0.5重量%〜1.5重量%の量で存在し、
前記溶媒成分が(R)−3−シクロペンチル−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]プロパンニトリルを溶解させることが可能な液体物質または液体物質の混合物であり、
前記医薬製剤が1つ以上の追加的医薬品と併用して投与される、
医薬製剤。 An oil-in-water emulsion containing water, an oil component, an emulsifier component, and a solvent component,
(R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile or a pharmaceutically acceptable salt thereof. A pharmaceutical formulation for topical dermal application for the treatment of skin disorders comprising a therapeutic agent, comprising:
The oil-in-water emulsion forms a cream,
The therapeutic agent is present in an amount of 0.5% to 1.5% by weight of the formulation, based on the free base,
The solvent component may dissolve (R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile. A possible liquid substance or mixture of liquid substances,
The pharmaceutical formulation is administered in combination with one or more additional pharmaceutical agents,
Pharmaceutical formulation.
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